Nitrogen-containing heterocyclic compound having inhibitory effect on production of kynurenine

ABSTRACT

The present invention provides a nitrogen-containing heterocyclic compound or a pharmaceutically acceptable salt thereof having an inhibitory effect on the production of kynurenine, represented by formula (I): 
     
       
         
         
             
             
         
       
     
     (wherein
 
R 6  and R 7  may be the same or different and each represent a hydrogen atom or the like,
 
R 8 , R 9 , R 10 , and R 11  may be the same or different and each represent a hydrogen atom or the like,
 
R 1  represents lower alkyl which may be substituted with cycloalkyl, or the like, and
 
R 3  represents optionally substituted aryl or an optionally substituted heterocyclic group).

TECHNICAL FIELD

The present invention relates to a nitrogen-containing heterocycliccompound having an inhibitory effect on the production of kynurenine ora pharmaceutically acceptable salt thereof; a kynurenine productioninhibitor comprising one or more of said compound or salt thereof as anactive ingredient; and the like.

BACKGROUND ART

Cancer cells excessively express tumor-associated antigens. The hostimmune system is considered to respond to the tumor-associated antigensand exert cellular immunity to eliminate the tumor. However, there existvarious types of immune escape mechanisms in the tumor microenvironmentor throughout the body, and when the host fails to eliminate the tumor,the tumor grows.

Recently it has been reported that indoleamine 2,3-dioxygenase (IDO),which is a tryptophan-metabolizing enzyme, inhibits the proliferation ofT cells and NK cells and activates regulatory T cells, thereby causingthe depression of the host immune system. The expression of IDO isincreased in tumor tissues and induced by IFN-γ stimulation in cancercells and dendritic cells (for example, J. Clin. Invest., vol. 117, No.5, pp. 1147-1154 (2007)). In a human body, 90% of an essential aminoacid, tryptophan, is metabolized into kynurenine and subsequently into30H-kynurenine, quinolinic acid, and the like in the kynurenine pathway,the initiation step of which involves IDO. Activation of IDO decreasesthe tryptophan concentration and increases the kynurenine concentrationin a local or systemic manner, and the tryptophan metabolites includingkynurenine induce the death of T cells and NK cells (for example, J.Exp. Med., vol. 196, No. 4, pp. 447-457 (2002)). The tryptophanmetabolism also induces the conversion of CD4⁺CD25⁻ T cells intoregulatory T cells (for example, Blood, vol. 109, No. 7, pp. 2871-2877(2007)). In the culture supernatant of dendritic cells in which theexpression of IDO is induced by INF-γ, the tryptophan concentration isdecreased and the kynurenine concentration is increased. When T cellsare co-cultured with such dendritic cells, T cell proliferation issuppressed compared to co-culture with unstimulated dendritic cells (forexample, J. Exp. Med., vol. 196, No. 4, pp. 447-457 (2002)).

From the above, in the tumor environment with an increased expression ofIDO, an increased kynurenine concentration induced by tryptophanmetabolism suppresses antitumor effector cells, which is considered tobe one of the immune escape mechanisms in tumors (for example, J. Clin.Invest., vol. 117, No. 5, pp. 1147-1154 (2007)).

An increased expression of IDO in the tumor tissues of colorectal cancerand prostate cancer has been reported (for example, Clin. Cancer Res.,vol. 12, No. 4, pp. 1144-1151 (2006); and Eur. J. Cancer, vol. 44, No.15, pp. 2266-2275 (2008)). In acute myeloid leukemia cells, IDO isconstantly expressed (for example, Leukemia, vol. 21, pp. 353-355(2007)). It has also been reported that when patients with endometrialcancer, melanoma or ovarian cancer has an increased expression of IDO,the patients will have a poor prognosis (for example, Br. J. Cancer,vol. 95, No. 11, pp. 1555-1561 (2006); J. Clin. Invest., vol. 114, No.2, pp. 280-290 (2004); and Clin. Cancer Res., vol. 11, No. 16, pp.6030-6039 (2005)). In adult T cell leukemia lymphoma and acute myeloidleukemia, the kynurenine/tryptophan ratio in the blood is increased (forexample, Leuk. Res., vol. 33, No. 1, pp. 39-45 (2009); and Leuk. Res.,vol. 33, No. 3, pp. 490-494 (2009)). It has also been reported thatmelanoma patients with an increased kynurenine/tryptophan ratio in theblood will have a poor prognosis (for example, Dermatology, vol. 214,No. 1, pp. 8-14 (2007)). As described above, IDO and/or kynurenine isconsidered to be involved in various types of solid cancers andhematologic cancers.

A tryptophan derivative, 1-methyltryptophan (1-MT), antagonizestryptophan, thereby inhibiting the production of kynurenine (forexample, Cancer Res., vol. 67, No. 2, pp. 792-800 (2007)). 1-MT cancelsthe suppression of T cell proliferation in the presence ofIDO-expressing cancer cells or IDO-expressing dendritic cells (forexample, Cancer Res., vol. 67, No. 2, pp. 792-800 (2007)). Further, 1-MTinduces major histocompatibility complex (MHC)-restricted rejection inallogeneic pregnant mice (for example, Nat. Immunol., vol. 2, No. 1, pp.64-68 (2001)). These results suggest that inhibition of IDO suppressesthe production of kynurenine and induces immunity.

1-MT shows an antitumor effect in tumor-bearing mice with mouse melanomacells. This effect disappears in immunodeficient mice (for example,Cancer Res., vol. 67, No. 2, pp. 792-800 (2007)). These results suggestthat the antitumor effect of 1-MT is based on immunostimulation by IDOinhibition-mediated inhibitory effect on the production of kynurenine.

In addition, compounds showing an inhibitory effect on the production ofkynurenine and/or on IDO are known to exhibit an immunostimulatoryeffect (for example, Nat. Immunol., vol. 2, pp. 64-68 (2001)).

It has been reported that the IDO expression in PBMC correlates with theviral load in HIV positive patients (for example, Blood, vol. 109, pp.3351-3359 (2007)). It has also been reported that chronic hepatitis Cpatients have an increased IDO mRNA level in the liver and an increasedserum kynurenine/tryptophan ratio (for example, J Virol., vol. 81, No.7, pp. 3662-3666 (2007)).

Further, compounds showing an inhibitory effect on the production ofkynurenine and/or on IDO are known to be useful as an antitumor agent,an anti-AIDS agent, an anti-AIDS dementia agent, anti-Alzheimer'sdisease agent, an antidepressant, and the like (for example, J ClinInvest., vol. 117, pp. 1147-1154 (2007); J Virol., vol. 81, pp.11593-11603 (2007); Neuropathol Appl Neurobiol., vol. 31, pp. 395-404(2005); Neurosci Lett., vol. 187, pp. 9-12 (1995); andNeuropsychopharmacology, vol. 33, pp. 2341-2351 (2008)).

As described above, IDO inhibitors and/or kynurenine productioninhibitors are considered to be promising preventive or therapeuticagents for diseases involving the production of kynurenine, such ascancers, AIDS, AIDS dementia, Alzheimer's disease, depression,infections, and immune diseases.

Pyrazine derivatives having an antagonistic effect on endothelin areknown (see Patent Literature 1 and Non Patent literature 1).

Compounds known as a therapeutic agent for diseases in which chemokinesare involved are N-pyrazinyl-2-thiophenesulfonamide derivatives (seePatent Literature 2), N-pyrazinylbenzenesulfonamide derivatives (seePatent Literature 3), N-(2-quinoxanyl)benzenesulfonamide derivatives(see Patent Literature 4), and the like. Compounds known as a chemokinereceptor antagonist are N-pyrazinylbenzenesulfonamide derivatives,N-(2-quinoxalinyl)benzenesulf onamide derivatives (see Patent Literature5 and 6), pyridopyrazin-2-on-3-ylmethanesulfonamide derivatives (seePatent Literature 7), and the like. Compounds known as a functionalmodulator of thymus and activation-regulated chemokine (TARC: CCchemokine ligand 17 (CCL17)) and/or of macrophage-derived chemokine(MDC: CC chemokine ligand 22 (CCL22)) are N-pyrazinylbenzenesulfonamidederivatives, N-(2-pyridopyrazinyl)benzenesulfonamide derivatives (seePatent Literature 8), and the like.

Compounds known for having an inhibitory activity onphosphatidylinositol-3-kinase (PI3K) areN-(2-quinoxanyl)benzenesulfonamide derivatives (see Patent Literatures 9and 10), and the like.

A nitrogen-containing heterocyclic compound having an inhibitory effecton the production of kynurenine (see Patent Literature 11) is alsoknown.

PRIOR ART Patent Literature

-   Patent Literature 1: JP 9-510987 T-   Patent Literature 2: WO 03/051870-   Patent Literature 3: WO 03/059893-   Patent Literature 4: WO 05/021513-   Patent Literature 5: WO 04/007472-   Patent Literature 6: WO 05/023771-   Patent Literature 7: WO 97/032858-   Patent Literature 8: JP 2006-137723 A-   Patent Literature 9: WO 07/044729-   Patent Literature 10: WO 07/023186-   Patent Literature 11: WO 2010/053182

Non Patent Literature

-   Non Patent Literature 1: Journal of Medicinal Chemistry, 1997, vol.    40, p. 996

SUMMARY OF INVENTION Problems to be Solved by Invention

An object of the present invention is to provide a nitrogen-containingheterocyclic compound having an inhibitory effect on the production ofkynurenine or a pharmaceutically acceptable salt thereof; a kynurenineproduction inhibitor comprising one or more of said compound or saltthereof as an active ingredient; and the like.

Means for Solving the Problems

The present invention relates to the following (1) to (20).

(1) A nitrogen-containing heterocyclic compound represented by formula(I):

(wherein

R⁶ and R⁷ may be the same or different and each represent a hydrogenatom, optionally substituted lower alkyl, optionally substitutedcycloalkyl, or optionally substituted aryl,

R⁸, R⁹, R¹⁰, and R¹¹ may be the same or different and each represent ahydrogen atom, halogen, cyano, optionally substituted lower alkyl,optionally substituted lower alkenyl, or optionally substituted loweralkynyl,

R¹ represents lower alkyl which may be substituted with cycloalkyl orlower alkyl which may be substituted with lower alkoxy, and

R³ represents optionally substituted aryl or an optionally substitutedheterocyclic group;

excluding the following cases:

(a) R¹ represents methyl, ethyl, propyl, isopropyl, butyl, isobutyl,sec-butyl, 2-methoxyethyl, or 3-methoxypropyl,

R³ represents pyridin-3-yl,R⁶ represents a hydrogen atom,R⁸, R⁹, R¹⁰, and R¹¹ each represent a hydrogen atom, andR⁷ represents trifluoromethyl;

-   -   (b) R¹ represents propyl,        R³ represents 1-methyl-1H-indol-2-yl, 6-methylpyridin-3-yl,        2-chlorothiazol-5-yl, 4-{(dimethylamino)methyl}phenyl,        4-cyanophenyl, tetrahydro-2H-pyran-4-yl, pyridine-1-oxide-3-yl,        1-methyl-2(1H)pyridon-5-yl,        tetrahydro-2H-thiopyran-1,1-dioxide-4-yl, thiazol-5-yl,        1-methyl-1H-imidazol-5-yl, 6-chloropyridin-3-yl,        2-methylpyridine-1-oxide-5-yl, 3-cyanophenyl, 4-chlorophenyl,        2-methylthiazol-5-yl, 1-methylpiperidin-4-yl, piperidin-4-yl,        1-acetylpiperidin-4-yl, 5-methylpyridin-3-yl,        5-fluoropyridin-3-yl, 1-methyl-2(1H)pyridon-4-yl,        5-methoxypyridin-3-yl, 5-chloropyridin-3-yl,        1-methanesulfonylpiperidin-4-yl,        1-methoxycarbonylpiperidin-4-yl, 1-propionylpiperidin-4-yl,        1-cyclopropylcarbonylpiperidin-4-yl, 2-methylthiazol-4-yl,        4-fluorotetrahydro-2H-pyran-4-yl,        4-cyanotetrahydro-2H-pyran-4-yl,        4-hydroxytetrahydro-2H-pyran-4-yl,        4-methoxytetrahydro-2H-pyran-4-yl,        1-acetyl-4-fluoropiperidin-4-yl,        4-fluoro-1-methanesulfonylpiperidin-4-yl,        1-acetyl-4-methylpiperidin-4-yl, or        1-methanesulfonyl-4-methylpiperidin-4-yl,        R⁶ represents a hydrogen atom,        R⁸, R⁹, R¹⁰, and R¹¹ each represent a hydrogen atom, and        R⁷ represents trifluoromethyl;

(c) R¹ represents propyl,

R³ represents pyridin-3-yl or pyridine-1-oxide-3-yl,R⁶ represents a hydrogen atom,R⁸, R⁹, R¹⁰, and R¹¹ each represent a hydrogen atom, andR⁷ represents isopropyl;

(d) R¹ represents propyl,

R³ represents 2-methylthiazol-5-yl,R⁸, R⁹, R¹⁰, and R¹¹ each represent a hydrogen atom, andR⁶ and R⁷ each represent a hydrogen atom; and

(e) R¹ represents cyclopropylmethyl,

R³ represents pyridin-3-yl, 6-methylpyridin-3-yl, 2-methylthiazol-5-yl,6-chloropyridin-3-yl, or 3-cyanophenyl,R⁶ represents a hydrogen atom,R⁸, R⁹, R¹⁰, and R¹¹ each represent a hydrogen atom, andR⁷ represents trifluoromethyl)or a pharmaceutically acceptable salt thereof.

(2) The nitrogen-containing heterocyclic compound or a pharmaceuticallyacceptable salt thereof according to (1), wherein R⁶ represents ahydrogen atom.

(3) The nitrogen-containing heterocyclic compound or a pharmaceuticallyacceptable salt thereof according to (1) or (2), wherein R⁷ representslower alkyl substituted with fluorine.

(4) The nitrogen-containing heterocyclic compound or a pharmaceuticallyacceptable salt thereof according to (1) or (2), wherein R⁷ representstrifluoromethyl.

(5) The nitrogen-containing heterocyclic compound or a pharmaceuticallyacceptable salt thereof according to any of (1) to (4), wherein R³represents an optionally substituted heterocyclic group.

(6) The nitrogen-containing heterocyclic compound or a pharmaceuticallyacceptable salt thereof according to any of (1) to (4), wherein R³represents optionally substituted pyridyl or an optionally substitutedbicyclic aromatic heterocyclic group.

(7) The nitrogen-containing heterocyclic compound or a pharmaceuticallyacceptable salt thereof according to any of (1) to (4), wherein R³represents optionally substituted pyridin-3-yl.

(8) The nitrogen-containing heterocyclic compound or a pharmaceuticallyacceptable salt thereof according to (7), wherein the substituent of theoptionally substituted pyridin-3-yl is a heterocyclic group which may besubstituted with lower alkyl.

(9) The nitrogen-containing heterocyclic compound or a pharmaceuticallyacceptable salt thereof according to any of (1) to (8), wherein R⁸, R⁹,R¹⁰, and R¹¹ may be the same or different and each represent a hydrogenatom, halogen, cyano, or lower alkynyl.

(10) The nitrogen-containing heterocyclic compound or a pharmaceuticallyacceptable salt thereof according to any of (1) to (8), wherein R⁸, R¹⁰,and R¹¹ each represent a hydrogen atom and R⁹ represents halogen, cyano,or lower alkynyl.

(11) The nitrogen-containing heterocyclic compound or a pharmaceuticallyacceptable salt thereof according to any of (1) to (8), wherein R¹ islower alkyl which may be substituted with cycloalkyl and Ra, R⁹, R¹⁰,and R¹¹ each represent a hydrogen atom.

(12) A pharmaceutical composition comprising, as an active ingredient,the nitrogen-containing heterocyclic compound or a pharmaceuticallyacceptable salt thereof described in any of (1) to (11).

(13) A kynurenine production inhibitor comprising, as an activeingredient, the nitrogen-containing heterocyclic compound or apharmaceutically acceptable salt thereof described in any of (1) to(11).

(14) A method for inhibiting the production of kynurenine, comprising astep of administering an effective amount of the nitrogen-containingheterocyclic compound or a pharmaceutically acceptable salt thereofdescribed in any of (1) to (11).

(15) Use of the nitrogen-containing heterocyclic compound or apharmaceutically acceptable salt thereof described in any of (1) to (11)for the manufacture of a kynurenine production inhibitor.

(16) The nitrogen-containing heterocyclic compound or a pharmaceuticallyacceptable salt thereof according to any of (1) to (11) for use ininhibiting the production of kynurenine.

(17) A preventive or therapeutic agent for a disease involving theproduction of kynurenine, comprising, as an active ingredient, thenitrogen-containing heterocyclic compound or a pharmaceuticallyacceptable salt thereof described in any of (1) to (11).

(18) A method for preventing or treating a disease involving theproduction of kynurenine, comprising a step of administering aneffective amount of the nitrogen-containing heterocyclic compound or apharmaceutically acceptable salt thereof described in any of (1) to(11).

(19) Use of the nitrogen-containing heterocyclic compound or apharmaceutically acceptable salt thereof described in any of (1) to (11)for the manufacture of a preventive or therapeutic agent for a diseaseinvolving the production of kynurenine.

(20) The nitrogen-containing heterocyclic compound or a pharmaceuticallyacceptable salt thereof according to any of (1) to (11) for use inpreventing or treating a disease involving the production of kynurenine.

Effects of Invention

The present invention provides a nitrogen-containing heterocycliccompound having an inhibitory effect on the production of kynurenine ora pharmaceutically acceptable salt thereof; a kynurenine productioninhibitor comprising one or more of said compound or salt thereof as anactive ingredient; and the like.

MODE FOR CARRYING OUT THE INVENTION

Hereinafter, the compound represented by the above formula (I) isreferred to as Compound (I). The same applies to the other compoundshaving different formula numbers.

The definitions of the respective groups in the formula (I) are asfollows.

(i) Examples of the lower alkyl and the lower alkyl moieties of thelower alkyl substituted with fluorine and the lower alkoxy includelinear or branched alkyl having 1 to 10 carbon atoms. More specificexamples thereof include methyl, ethyl, n-propyl, isopropyl, n-butyl,isobutyl, sec-butyl, tert-butyl, n-pentyl, neopentyl, n-hexyl, n-heptyl,n-octyl, n-nonyl, n-decyl, and the like.(i-1) Examples of the lower alkenyl include linear or branched alkenylhaving 2 to 10 carbon atoms. More specific examples thereof includevinyl, allyl, 1-propenyl, butenyl, pentenyl, hexenyl, heptenyl, octenyl,nonenyl, decenyl, and the like.(i-2) Examples of the lower alkynyl include linear or branched alkynylhaving 2 to 10 carbon atoms. More specific examples thereof includeethynyl, propynyl, butynyl, pentynyl, hexynyl, heptynyl, octynyl,nonynyl, decynyl, and the like.(ii) Examples of the cycloalkyl include cycloalkyl having 3 to 10 carbonatoms. More specific examples thereof include cyclopropyl, cyclobutyl,cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclodecyl,noradamantyl, adamantyl, bicyclo[2,2,1]heptyl, bicyclo[2,2,2]octyl,bicyclo[3,3,0]octyl, bicyclo[3,3,1]nonyl, and the like.(iii) Examples of the aryl include monocyclic aryl and fused aryl inwhich two or more rings are fused. More specific examples thereofinclude aryl having 6 to 14 ring carbon atoms, such as phenyl, naphthyl,indenyl, and anthranil.(iv) Examples of the heterocyclic group include an aromatic heterocyclicgroup, an aliphatic heterocyclic group, and the like.

Examples of the aromatic heterocyclic group include a 5- or 6-memberedmonocyclic aromatic heterocyclic group which contains at least oneheteroatom selected from a nitrogen atom, an oxygen atom and a sulfuratom; a bicyclic aromatic heterocyclic group in which 3- to 8-memberedrings are fused and which contains at least one heteroatom selected froma nitrogen atom, an oxygen atom and a sulfur atom; a tricyclic aromaticheterocyclic group in which 3- to 8-membered rings are fused and whichcontains at least one heteroatom selected from a nitrogen atom, anoxygen atom and a sulfur atom; and the like. More specific examplesthereof include furyl, thienyl, pyrrolyl, imidazolyl, pyrazolyl,oxazolyl, isoxazolyl, oxadiazolyl, thiazolyl, isothiazolyl,thiadiazolyl, triazolyl, tetrazolyl, pyridyl, pyridyl-1-oxide,pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, benzofuranyl,benzothiophenyl, benzoxazolyl, benzoxadiazolyl benzothiazolyl,isoindolyl, indolyl, indazolyl, benzimidazolyl, benzotriazolyl,oxazolopyrimidinyl, thiazolopyrimidinyl, pyrrolopyridyl,pyrrolopyrimidinyl, imidazopyridyl, imidazopyrimidinyl, triazolopyridyl,triazolopyrimidinyl, purinyl, quinolinyl, isoquinolinyl, cinnolinyl,phthalazinyl, quinazolinyl, quinoxalinyl, naphthyridinyl, and the like.Among these, preferred as the bicyclic aromatic heterocyclic groups arebenzofuranyl, benzothiophenyl, benzoxazolyl, benzoxadiazolyl,benzothiazolyl, isoindolyl, indolyl, indazolyl, benzimidazolyl,benzotriazolyl, oxazolopyrimidinyl, thiazolopyrimidinyl, pyrrolopyridyl,pyrrolopyrimidinyl, imidazopyridyl, imidazopyrimidinyl, triazolopyridyl,triazolopyrimidinyl, purinyl, quinolinyl, isoquinolinyl, cinnolinyl,phthalazinyl, quinazolinyl, quinoxalinyl, naphthyridinyl, and the like.

Examples of the aliphatic heterocyclic group include a 5- or 6-memberedmonocyclic aliphatic heterocyclic group which contains at least oneheteroatom selected from a nitrogen atom, an oxygen atom and a sulfuratom; a bicyclic or tricyclic fused aliphatic heterocyclic group inwhich 3- to 8-membered rings are fused and which contains at least oneheteroatom selected from a nitrogen atom, an oxygen atom and a sulfuratom; and the like. More specific examples thereof include aziridinyl,azetidinyl, pyrrolidinyl, piperidino, piperidinyl, quinuclidinyl,azepanyl, 1,2,5,6-tetrahydropyridyl, 1,2-dihydropyridyl, imidazolidinyl,pyrazolidinyl, piperazinyl, homopiperazinyl, pyrazolinyl, oxiranyl,oxetanyl, tetrahydrofuranyl, tetrahydro-2H-pyranyl,5,6-dihydro-2H-pyranyl, 1,4-dioxanyl, 1,3-dioxanyl,tetrahydro-2H-thiopyranyl, tetrahydro-2H-thiopyranyl-1,1-dioxide,tetrahydro-2H-thiopyranyl-1-oxide, oxazolidinyl, morpholino,morpholinyl, thioxazolidinyl, thiomorpholinyl, 2H-oxazolyl,2H-thioxazolyl, dihydroindolyl, dihydroisoindolyl, dihydrobenzofuranyl,benzimidazolidinyl, dihydrobenzoxazolyl, dihydrobenzothioxazolyl,3,4-dihydro-2H-benzo[b][1,4]oxazinyl, 2,3-dihydrobenzo[b][1,4]dioxinyl,benzo[d][1,3]dioxolyl, tetrahydroquinolyl, tetrahydroisoquinolyl,chromanyl, thiochromanyl, tetrahydroquinoxalinyl,tetrahydroquinazolinyl, and the like.

(v) Halogen means each atom of a fluorine atom, a chlorine atom, abromine atom, and an iodine atom.(x) The substituents of the optionally substituted lower alkyl, theoptionally substituted lower alkenyl, the optionally substituted loweralkynyl, and the optionally substituted cycloalkyl may be the same ordifferent and the number of the substituents of these groups is from 1to the highest possible number of substitution, preferably 1 to 3, andexamples of the substituents include a substituent selected from thegroup consisting of:

(x-a) halogen,

(x-b) hydroxy,

(x-c) cyano,

(x-d) carboxy,

(x-e) optionally substituted lower alkoxycarbonyl (the number of thesubstituents of the optionally substituted lower alkoxycarbonyl is 1 to3 and examples of the substituents include a substituent selected fromthe group consisting of halogen, hydroxy, sulfanyl, nitro, cyano,carboxy, carbamoyl, cycloalkyl, aryl, an aliphatic heterocyclic group,an aromatic heterocyclic group, lower alkoxy, cycloalkoxy, aryloxy,aralkyloxy, lower alkanoyloxy, aroyloxy, lower alkylsulfanyl,—NR^(X)R^(Y) (wherein R^(X) and R^(Y) may be the same or different andeach represent a hydrogen atom, lower alkyl, cycloalkyl, aryl, anaromatic heterocyclic group, aralkyl, lower alkanoyl, aroyl, loweralkoxycarbonyl, aralkyloxycarbonyl, or the like), lower alkanoyl, aroyl,lower alkoxycarbonyl, aryloxycarbonyl, lower alkylcarbamoyl, di-loweralkylcarbamoyl, and the like),

(x-f) optionally substituted cycloalkyl (the number of the substituentsof the optionally substituted cycloalkyl is 1 to 3 and examples of thesubstituents include a substituent selected from the group consisting ofoxo, halogen, hydroxy, sulfanyl, nitro, cyano, carboxy, carbamoyl, loweralkyl, trifluoromethyl, cycloalkyl, aryl, an aliphatic heterocyclicgroup, an aromatic heterocyclic group, lower alkoxy, cycloalkoxy,aryloxy, aralkyloxy, lower alkanoyloxy, aroyloxy, lower alkylsulfanyl,—NR^(X1)R^(Y1) (wherein R^(X1) and R^(Y1) may be the same or differentand each represent a hydrogen atom, lower alkyl, cycloalkyl, aryl, anaromatic heterocyclic group, aralkyl, lower alkanoyl, aroyl, loweralkoxycarbonyl, aralkyloxycarbonyl, or the like), lower alkanoyl, aroyl,lower alkoxycarbonyl, aryloxycarbonyl, lower alkylcarbamoyl, di-loweralkylcarbamoyl, and the like),

(x-g) optionally substituted lower alkoxy (examples of the substituentsof the optionally substituted lower alkoxy include the groupsexemplified in the above substituents of the optionally substitutedlower alkoxycarbonyl (x-e), and the like),

(x-h) optionally substituted aryl (the number of the substituents of theoptionally substituted aryl is 1 to 3 and examples of the substituentsinclude a substituent selected from the group consisting of halogen,hydroxy, sulfanyl, nitro, cyano, carboxy, carbamoyl, lower alkyl,trifluoromethyl, cycloalkyl, an aliphatic heterocyclic group, anaromatic heterocyclic group, lower alkoxy, cycloalkoxy, aryloxy,aralkyloxy, lower alkanoyloxy, aroyloxy, lower alkylsulfanyl, loweralkylsulfinyl, lower alkylsulfonyl, —NR^(X2)R^(Y2) (wherein R^(X2) andR^(Y2) may be the same or different and each represent a hydrogen atom,lower alkyl, cycloalkyl, aryl, an aromatic heterocyclic group, aralkyl,lower alkanoyl, aroyl, lower alkoxycarbonyl, aralkyloxycarbonyl, or thelike), lower alkanoyl, aroyl, lower alkoxycarbonyl, aryloxycarbonyl,lower alkylcarbamoyl, di-lower alkylcarbamoyl, and the like),

(x-i) an optionally substituted heterocyclic group {examples of thesubstituents of the optionally substituted heterocyclic group includethe groups exemplified in the substituents of the above optionallysubstituted aryl (x-h), and the like and, when the heterocyclic group ofthe optionally substituted heterocyclic group is an aliphaticheterocyclic group, the examples also include oxo, and the like},

(x-j) —NR³¹R³² {wherein R³1 and R³² may be the same or different andeach represent a hydrogen atom, lower alkoxycarbonyl, lower alkenyl,lower alkynyl, lower alkanoyl, optionally substituted lower alkyl(examples of the substituents of the optionally substituted lower alkylinclude the groups exemplified in the substituents of the aboveoptionally substituted lower alkoxycarbonyl (x-e), and the like),optionally substituted cycloalkyl (examples of the substituents of theoptionally substituted cycloalkyl include the groups exemplified in thesubstituents of the above optionally substituted cycloalkyl (x-f), andthe like), optionally substituted aryl (examples of the substituents ofthe optionally substituted aryl include the groups exemplified in thesubstituents of the above optionally substituted aryl (x-h), and thelike), an optionally substituted heterocyclic group (examples of thesubstituents of the optionally substituted heterocyclic group includethe groups exemplified in the substituents of the above optionallysubstituted heterocyclic group (x-i), and the like)},

(x-k) —CONR³³R³⁴ {wherein R³³ and R³⁴ may be the same or different andeach represent a hydrogen atom, optionally substituted lower alkyl(examples of the substituents of the optionally substituted lower alkylinclude the groups exemplified in the substituents of the aboveoptionally substituted lower alkoxycarbonyl (x-e), and the like),optionally substituted cycloalkyl (examples of the substituents of theoptionally substituted cycloalkyl include the groups exemplified in thesubstituents of the above optionally substituted cycloalkyl (x-f), andthe like), lower alkanoyl, or the like; or R³³ and R³⁴ are combinedtogether with the adjacent nitrogen atom to form a nitrogen-containingheterocyclic group},

(x-l) optionally substituted lower alkylsulfonyl (examples of thesubstituents of the optionally substituted lower alkylsulfonyl includethe groups exemplified in the substituents of the above optionallysubstituted lower alkoxycarbonyl (x-e), and the like), and

(x-m) tri(lower alkyl)silyloxy,

and the like.

Examples of the substituents of the optionally substituted cycloalkylalso include lower alkyl, and the like in addition to the abovesubstituents.

(xi) The substituents of the optionally substituted aryl, the optionallysubstituted pyridyl, the optionally substituted pyridin-3-yl, theoptionally substituted bicyclic aromatic heterocyclic group, and theoptionally substituted heterocyclic group may be the same or differentand the number of the substituents of these groups is 1 to 3 andexamples of the substituents include a substituent selected from thegroup consisting of:

(xi-a) halogen,

(xi-b) hydroxy,

(xi-c) cyano,

(xi-d) formyl,

(xi-e) carboxy,

(xi-f) optionally substituted lower alkoxycarbonyl (examples of thesubstituents of the optionally substituted lower alkoxycarbonyl includethe groups exemplified in the substituents (x) of the above optionallysubstituted lower alkyl, and the like, and the like),

(xi-g) optionally substituted lower alkyl (examples of the substituentsof the optionally substituted lower alkyl include the groups exemplifiedin the substituents (x) of the above optionally substituted lower alkyl,and the like, and the like),

(xi-h) optionally substituted lower alkoxy (examples of the substituentsof the optionally substituted lower alkoxy include the groupsexemplified in the substituents (x) of the above optionally substitutedlower alkyl, and the like, and the like),

(xi-i) optionally substituted lower alkanoyl (examples of thesubstituents of the optionally substituted lower alkanoyl include thegroups exemplified in the substituents (x) of the above optionallysubstituted lower alkyl, and the like, and the like),

(xi-j) optionally substituted lower alkylsulfanyl (examples of thesubstituents of the optionally substituted lower alkylsulfanyl includethe groups exemplified in the substituents (x) of the above optionallysubstituted lower alkyl, and the like, and the like),

(xi-k) optionally substituted lower alkylsulfinyl (examples of thesubstituents of the optionally substituted lower alkylsulfinyl includethe groups exemplified in the substituents (x) of the above optionallysubstituted lower alkyl, and the like, and the like),

(xi-l) optionally substituted lower alkylsulfonyl (examples of thesubstituents of the optionally substituted lower alkylsulfonyl includethe groups exemplified in the substituents (x) of the above optionallysubstituted lower alkyl, and the like, and the like),

(xi-m) optionally substituted aryl (examples of the substituents of theoptionally substituted aryl include the groups exemplified in thesubstituents of the above optionally substituted aryl (x-h), and thelike),

(xi-n) an optionally substituted heterocyclic group (examples of thesubstituents of the optionally substituted heterocyclic group includethe groups exemplified in the substituents of the above optionallysubstituted heterocyclic group (x-i), and the like),

(xi-o) —NR³⁵R³⁶ {wherein R³⁵ and R³⁶ may be the same or different andeach represent a hydrogen atom, optionally substituted lower alkyl(examples of the substituents of the optionally substituted lower alkylinclude the groups exemplified in the substituents (x) of the aboveoptionally substituted lower alkyl, and the like, and the like),optionally substituted lower alkanoyl (examples of the substituents ofthe optionally substituted lower alkanoyl include the groups exemplifiedin the substituents (x) of the above optionally substituted lower alkyl,and the like, and the like), optionally substituted lower alkoxycarbonyl(examples of the substituents of the optionally substituted loweralkoxycarbonyl include the groups exemplified in the substituents (x) ofthe above optionally substituted lower alkyl, and the like, and thelike), carbamoyl, optionally substituted lower alkylcarbamoyl (examplesof the substituents of the optionally substituted lower alkylcarbamoylinclude the groups exemplified in the substituents (x) of the aboveoptionally substituted lower alkyl, and the like, and the like),optionally substituted di-lower alkylcarbamoyl (examples of thesubstituents of the optionally substituted di-lower alkylcarbamoylinclude the groups exemplified in the substituents (x) of the aboveoptionally substituted lower alkyl, and the like, and the like),optionally substituted aryl (examples of the substituents of theoptionally substituted aryl include the groups exemplified in thesubstituents of the above optionally substituted aryl (x-h), and thelike), or the like},

(xi-p) —CONR³⁷R³⁸ {wherein R³⁷ and R³⁸ may be the same or different andeach represent a hydrogen atom, optionally substituted lower alkyl(examples of the substituents of the optionally substituted lower alkylinclude the groups exemplified in the substituents (x) of the aboveoptionally substituted lower alkyl, and the like, and the like),optionally substituted aryl (examples of the substituents of theoptionally substituted aryl include the groups exemplified in thesubstituents of the above optionally substituted aryl (x-h), and thelike), or the like; or R³⁷ and R³⁸ are combined together with theadjacent nitrogen atom to form an optionally substitutednitrogen-containing heterocyclic group (examples of the substituents ofthe optionally substituted nitrogen-containing heterocyclic group formedtogether with the adjacent nitrogen atom include the groups exemplifiedin the substituents of the above optionally substituted heterocyclicgroup (x-i), and the like)},

(xi-q) optionally substituted cycloalkyl (examples of the substituentsof the optionally substituted cycloalkyl include the groups exemplifiedin the substituents (x-f) of the above optionally substitutedcycloalkyl, and the like), and the like.

Examples of the substituents of the optionally substituted heterocyclegroup also include, in addition to the groups exemplified in thesubstituents of the above (xi-a) to (xi-q), the number of thesubstituents being 1 to 3,

(xi-r) oxo,

(xi-s) —O(CR³⁹R⁴⁰)_(n)O— (wherein R³⁹ and R⁴⁰ may be the same ordifferent and each represent a hydrogen atom, lower alkyl, or the like;n represents an integer of 1 to 3; and the two terminal oxygen atoms arebound to the same carbon atom in the heterocyclic group), and

(xi-t) optionally substituted cycloalkylcarbonyl (examples of thesubstituents of the optionally substituted cycloalkylcarbonyl includehalogen, amino, hydroxy, and the like, the number of the substituentsbeing 1 to 3).

(xii) Examples of the lower alkyl substituted with fluorine includelower alkyl substituted with a fluorine atom(s), the number of which isfrom 1 to the highest possible number of substitution, and the like.More specific examples thereof include trifluoromethyl,(1-fluoro-1-methyl)ethyl, 1,1,2,2,2-pentafluoroethyl, and the like.

In the groups exemplified in the above (x) to (xii), the lower alkyl andthe lower alkyl moieties of the lower alkoxy, the lower alkoxycarbonyl,the lower alkanoyl, the lower alkanoyloxy, the lower alkylcarbamoyl, thedi-lower alkylcarbamoyl, the lower alkylsulfanyl, the loweralkylsulfinyl, the lower alkylsulfonyl, and the tri-(lower alkyl)silyloxy have the same meanings as defined in the above lower alkyl (i).The two lower alkyl moieties of the di-lower alkyl carbamoyl may be thesame or different, and the three lower alkyl moieties of the tri-(loweralkyl) silyloxy may be the same or different. The lower alkenyl has thesame meaning as defined in the above (i-1) lower alkenyl. The loweralkynyl has the same meaning as defined in the above (i-2) loweralkynyl. The cycloalkyl and the cycloalkyl moieties of the cycloalkoxyand the cycloalkylcarbonyl have the same meanings as defined in theabove cycloalkyl (ii). The aryl and the aryl moieties of the aryloxy,the aralkyl, the aralkyloxy, the aralkyloxycarbonyl, thearyloxycarbonyl, the aroyl, and the aroyloxy have the same meanings asdefined in the above aryl (iii). Examples of the alkylene moieties ofthe aralkyl, the aralkyloxy, and the aralkyloxycarbonyl include analkylene group which is derived from the groups exemplified in the abovelower alkyl (i) by removing one hydrogen atom. The halogen has the samemeaning as defined in the above halogen (v). The heterocyclic group hasthe same meaning as defined in the above heterocyclic group (iv). Thealiphatic heterocyclic group refers to the aliphatic heterocyclic groupsexemplified in the above heterocyclic group (iv). The aromaticheterocyclic group refers to the aromatic heterocyclic groupsexemplified in the above heterocyclic group (iv). Examples of thenitrogen-containing heterocyclic group formed together with the adjacentnitrogen atom include a 5- or 6-membered monocyclic heterocyclic groupwhich contains at least one nitrogen atom (the monocyclic heterocyclicgroup may contain a further nitrogen atom, an oxygen atom, or a sulfuratom), a bicyclic or tricyclic fused heterocyclic group in which 3- to8-membered rings are fused and which contains at least one nitrogen atom(the fused heterocyclic group may contain a further nitrogen atom, anoxygen atom, or a sulfur atom), and the like. More specific examplesthereof include aziridinyl, azetidinyl, pyrrolidinyl, piperidino,azepanyl, pyrrolyl, imidazolidinyl, imidazolyl, pyrazolidinyl,pyrazolinyl, pyrazolyl, piperazinyl, homopiperazinyl, oxazolidinyl,2H-oxazolyl, thioxazolidinyl, 2H-thioxazolyl, morpholino,thiomorpholinyl, dihydroindolyl, dihydroisoindolyl, indolyl, isoindolyl,tetrahydroquinolyl, tetrahydroisoquinolyl, dihydrobenzoxazolyl,dihydrobenzothioxazolyl, benzimidazolidinyl, benzimidazolyl,dihydroindazolyl, indazolyl, benzotriazolyl, pyrrolopyridyl,pyrrolopyrimidinyl, imidazopyridyl, purinyl, and the like.

Examples of a pharmaceutically acceptable salt of Compound (I) includepharmaceutically acceptable acid addition salts, metal salts, ammoniumsalts, organic amine addition salts, amino acid addition salts, and thelike. Examples of the acid addition salts include inorganic acid saltssuch as hydrochlorides, sulfates, and phosphates; organic acid saltssuch as acetates, trifluoroacetates, maleates, fumarates, tartrates,citrates, and lactates; and the like. Examples of the metal saltsinclude alkali metal salts such as sodium salts and potassium salts;alkaline earth metal salts such as magnesium salts and calcium salts;aluminum salts; zinc salts; and the like. Examples of the ammonium saltsinclude salts of ammonium, tetramethylammonium, and the like. Examplesof the organic amine addition salts include addition salts ofmorpholine, piperidine, and the like. Examples of the amino acidaddition salts include addition salts of lysine, glycine, phenylalanine,aspartic acid, glutamic acid, and the like.

When one or more of Compound (I) or a pharmaceutically acceptable saltthereof used in the present invention are (1) added to cells and thelike in an in vitro system or (2) administered to a living body such asmammals, the production of kynurenine is inhibited in an in vitro systemor a living body, in comparison with the case where the compound or apharmaceutically acceptable salt thereof is not administered. That is,Compound (I) and a pharmaceutically acceptable salt thereof have aninhibitory effect on the production of kynurenine and consequently havean inhibitory effect on the increase in the kynurenine level. Compound(I) and a pharmaceutically acceptable salt thereof have an excellentinhibitory effect on the production of kynurenine and therefore areuseful for, for example, prevention or treatment of a disease in whichIDO and/or kynurenine is involved. Compound (I) and a pharmaceuticallyacceptable salt thereof are especially suitable as an active ingredientof a preventive or therapeutic agent for a disease involving theproduction of kynurenine, for example, a disease in which the local orsystemic level of kynurenine is increased, and also as an activeingredient of a kynurenine production inhibitor. In particular, Compound(I) and a pharmaceutically acceptable salt thereof are suitable as anactive ingredient of a preventive or therapeutic agent for diseases suchas cancers (tumors), immune diseases, neurodegenerative diseases, andinfections.

“Treatment” refers to alleviating or curing a condition or a diseaseand/or its accompanying symptom, and to alleviating the same.“Prevention” refers to delaying or preventing the development of acondition or a disease and its accompanying symptom, or to reducing thesubject's risk of developing a condition or a disease.

Examples of the disease involving the production of IDO and/orkynurenine include cancers (tumors), immune diseases, neurodegenerativediseases, infections, and the like.

Examples of the cancers (tumors) include hematopoietic tumor, multiplemyeloma, breast cancer, ovarian cancer, endometrial cancer, cervicalcancer, prostate cancer, bladder cancer, renal cancer, gastric cancer,esophagus cancer, hepatic cancer, biliary tract cancer, colon cancer,rectal cancer, pancreatic cancer, lung cancer, head and neck cancer,osteosarcoma, melanoma, brain tumor, and the like. In particular,Compound (I) and a pharmaceutically acceptable salt thereof are suitablefor prevention or treatment of gastric cancer, breast cancer, and thelike.

Examples of the immune diseases include acquired immune deficiencysyndrome (AIDS), bronchial asthma, pollen allergy, allergic rhinitis,atopic dermatitis, rheumatoid arthritis, ulcerative colitis, Crohn'sdisease, multiple sclerosis, amyotrophic lateral sclerosis, graft versushost disease, and the like.

Examples of the neurodegenerative diseases include AIDS dementia,Alzheimer's disease, depression, and the like.

Examples of the infections include viral infection, bacterial infection,fungal infection, chlamydial infection, rickettsial infection, and thelike.

The above Compound (I) and a pharmaceutically acceptable salt thereofare especially suitable as an active ingredient for a preventive ortherapeutic agent for cancers (tumors), and the like.

Hereinafter, production methods of Compound (I) will be described.

In the production methods described below, in cases where a definedgroup changes under the conditions of the implementation methods or isnot suitable for carrying out the production methods, a method commonlyused in synthetic organic chemistry for introducing and removing aprotective group (for example, the method described in T. W. Greene,Protective Groups in Organic Synthesis, 3rd edition, John Wiley & SonsInc. (1999), or the like), and the like may be used to produce a desiredcompound. The order of the reaction steps, such as introduction of asubstituent, may be changed as necessary.

Compound (I) can be produced, for example, according to the followingProduction Methods 1 to 5.

Production Method 1

(In the formula, R¹, R³, R⁶, R⁷, R⁸, R⁹, R¹⁰ and R¹¹ have the samemeanings as defined above, respectively, and Z¹ and Z² may be the sameor different and each represent a leaving group, such as a chlorineatom, a bromine atom, an iodine atom, methanesulfonyloxy,p-toluenesulfonyloxy, and trifluoromethanesulfonyloxy.)

Step 1

Compound (Va-1) can be produced by reacting Compound (IIIa-1) with 1 to10 equivalents, preferably 1 equivalent, of Compound (IV) in the absenceof a solvent or in a solvent inert to the reaction in the presence of 1to 100 equivalents, preferably 1 to 5 equivalents, of a suitable base ata temperature between −10° C. and 200° C., preferably between 30° C. and180° C., for 5 minutes to 72 hours.

Examples of the solvent inert to the reaction include tetrahydrofuran(THF), dioxane, 1,2-dimethoxyethane, benzene, toluene, xylene,N,N-dimethylformamide (DMF), N,N-dimethylacetamide (DMA), dimethylsulfoxide (DMSO), N-methylpyrrolidone (NMP), pyridine, chloroform,dichloromethane, ethyl acetate, acetonitrile, and the like. Thesesolvents can be used alone or as a mixture thereof. Among these,preferred is DMSO or DMF.

Examples of the suitable base include alkali metal hydrides, such assodium hydride and potassium hydride; metal alkoxides, such as sodiummethoxide, sodium ethoxide and potassium tert-butoxide; organometallicbases, such as n-butyllithium, sec-butyllithium and tert-butyllithium;metal amides, such as lithium diisopropylamide (LDA) and lithiumhexamethyldisilazane (LiHMDS); alkali metal salts, such as sodiumhydroxide, potassium hydroxide, lithium hydroxide, sodium carbonate andpotassium carbonate; organic bases, such as pyridine, triethylamine,diisopropylethylamine, 1,8-diazabicyclo[5,4,0]undec-7-ene (DBU),1,5-diazabicyclo[4,3,0]non-5-ene (DBN), N,N-dimethylaminopyridine (DMAP)and N-methylmorpholine; solid bases, such as AMBERLYST A-21 (Rohm andHaas Company), AG1-X8 (Bio-Rad Laboratories, Inc.), polyvinylpyridineand morpholinomethyl polystyrene; and the like. Among these, preferredare alkali metal hydrides, alkali metal salts, and the like. Morepreferred are sodium hydride, potassium carbonate, and the like.

Compound (IIIa-1) can be obtained, for example, as a commercial product,or according to known methods (for example, the method described in WO2003/059893, Journal of Medicinal Chemistry, vol. 24, pp. 93-101 (1981),and the like).

Compound (IV) can be obtained, for example, as a commercial product.

Step 2

Compound (I) can be produced by reacting Compound (Va-1) with 1 to 20equivalents, preferably 1 to 4 equivalents, of Compound (VI) in theabsence of a solvent or in a solvent inert to the reaction in thepresence of 1 to 100 equivalents, preferably 1 to 10 equivalents, of asuitable base at a temperature between −20° C. and 200° C., preferablybetween room temperature and 80° C., for 5 minutes to 72 hours.

Examples of the solvent inert to the reaction include THF, dioxane,1,2-dimethoxyethane, benzene, toluene, xylene, DMF, DMA, NMP, pyridine,chloroform, dichloromethane, ethyl acetate, acetonitrile, and the like.These solvents can be used alone or as a mixture thereof. Among these,preferred is THF or DMF.

Examples of the suitable base include alkali metal hydrides, such assodium hydride and potassium hydride; metal alkoxides, such as sodiummethoxide, sodium ethoxide and potassium tert-butoxide; organometallicbases, such as n-butyllithium, sec-butyllithium and tert-butyllithium;metal amides, such as LDA and LiHMDS; alkali metal salts, such as sodiumhydroxide, potassium hydroxide, lithium hydroxide, sodium carbonate andpotassium carbonate; organic bases, such as pyridine, triethylamine,diisopropylethylamine, DBU, DBN, DMAP and N-methylmorpholine; solidbases, such as AMBERLYST A-21 (Rohm and Haas Company), AG1-X8 (Bio-RadLaboratories, Inc.), polyvinylpyridine and morpholinomethyl polystyrene;and the like. Among these, preferred are alkali metal hydrides, metalalkoxides, and the like. More preferred are sodium hydride, potassiumtert-butoxide, and the like.

Compound (VI) can be obtained according to known methods (For example,Journal of the American Chemical Society, vol. 111, p. 393 (1989), andthe like), or as a commercial product.

Production Method 2

(In the formula, R¹, R³, R⁶, R⁷, R⁸, R⁹, R¹⁰, R¹¹, Z¹ and Z² have thesame meanings as defined above, respectively.)

Step 1

Compound (VIIa-1) can be produced from Compound (IIIa-1) in the samemanner as in Step 2 of Production Method 1.

Step 2

Compound (I) can be produced from Compound (VIIa-1) in the same manneras in Step 1 of Production Method 1.

Production Method 3

(In the formula, R¹, R³, R⁶, R⁷, R⁸, R⁹, R¹⁰, R¹¹ and Z² have the samemeanings as defined above, respectively, and Z³ represents a leavinggroup, such as a chlorine atom, a bromine atom, an iodine atom,methanesulfonyloxy, p-toluenesulfonyloxy, ortrifluoromethanesulfonyloxy.)

Step 1

Compound (Va-2) can be produced by reacting Compound (IIIa-2) with 1 to10 equivalents, preferably 1 equivalent, of Compound (VIII) in theabsence of a solvent or in a solvent inert to the reaction in thepresence of 1 to 100 equivalents, preferably 1 to 5 equivalents, of asuitable base at a temperature between −10° C. and 200° C., preferablybetween 30° C. and 180° C., for 5 minutes to 72 hours.

Examples of the solvent inert to the reaction include THF, dioxane,1,2-dimethoxyethane, benzene, toluene, xylene, DMF, DMA, DMSO, NMP,pyridine, chloroform, dichloromethane, ethyl acetate, acetonitrile, andthe like. These solvents can be used alone or as a mixture thereof.Among these, preferred are DMSO, DMF, and the like.

Examples of the suitable base include alkali metal hydrides, such assodium hydride and potassium hydride; metal alkoxides, such as sodiummethoxide, sodium ethoxide and potassium tert-butoxide; organometallicbases, such as n-butyllithium, sec-butyllithium and tert-butyllithium;metal amides, such as LDA and LiHMDS; alkali metal salts, such as sodiumhydroxide, potassium hydroxide, lithium hydroxide, sodium carbonate andpotassium carbonate; organic bases, such as pyridine, triethylamine,diisopropylethylamine, DBU, DBN, DMAP and N-methylmorpholine; solidbases, such as AMBERLYST A-21 (Rohm and Haas Company), AG1-X8 (Bio-RadLaboratories, Inc.), polyvinylpyridine and morpholinomethyl polystyrene;and the like. Among these, preferred are alkali metal hydrides. Morepreferred is sodium hydride, or the like.

Compound (IIIa-2) can be obtained, for example, as a commercial product,or according to known methods (for example, the method described in U.S.Pat. No. 3,898,216, WO 2010124826, or the like).

Compound (VIII) can be obtained, for example, as a commercial product.

Step 2

Compound (I) can be produced by reacting Compound (Va-2) with 1 to 20equivalents, preferably 1 to 4 equivalents, of Compound (VI) in theabsence of a solvent or in a solvent inert to the reaction in thepresence of 1 to 100 equivalents, preferably 1 to 10 equivalents, of asuitable base at a temperature between −20° C. and 200° C., preferablybetween room temperature and 80° C., for 5 minutes to 72 hours.

Examples of the solvent inert to the reaction include THF, dioxane,1,2-dimethoxyethane, benzene, toluene, xylene, DMF, DMA, NMP, pyridine,chloroform, dichloromethane, ethyl acetate, acetonitrile, and the like.These solvents can be used alone or as a mixture thereof. Among these,preferred are THF, DMF, and the like.

Examples of the suitable base include alkali metal hydrides, such assodium hydride and potassium hydride; metal alkoxides, such as sodiummethoxide, sodium ethoxide and potassium tert-butoxide; organometallicbases, such as n-butyllithium, sec-butyllithium and tert-butyllithium;metal amides, such as LDA and LiHMDS; alkali metal salts, such as sodiumhydroxide, potassium hydroxide, lithium hydroxide, sodium carbonate andpotassium carbonate; organic bases, such as pyridine, triethylamine,diisopropylethylamine, DBU, DBN, DMAP and N-methylmorpholine; solidbases, such as AMBERLYST A-21 (Rohm and Haas Company), AG1-X8 (Bio-RadLaboratories, Inc.), polyvinylpyridine and morpholinomethyl polystyrene;and the like. Among these, preferred are alkali metal hydrides, metalalkoxides, and the like. More preferred are sodium hydride, potassiumtert-butoxide, and the like.

Production Method 4

(In the formula, R¹, R³, R⁶, R⁷, R⁸, R⁹, R¹¹, Z² and Z³ have the samemeanings as defined above, respectively.)

Step 1

Compound (IXa-1) can be produced from Compound (IIIa-2) in the samemanner as in Step 2 of Production Method 3.

Step 2

Compound (I) can be produced from Compound (IXa-1) in the same manner asin Step 1 of Production Method 3.

Production Method 5

(In the formula, R¹, R³, R⁶, R⁷, R⁸, R⁹, R¹⁰, R¹¹, Z² and Z³ have thesame meanings as defined above, respectively.)

Step 1

Compound (XIIa-1) can be produced from Compound (IIIa-3) in the samemanner as in Step 2 of Production Method 3.

Step 2

Compound (XIa-1) can be produced by treating Compound (XIIa-1) with 10to 100% by weight of a reducing agent in the absence of a solvent or ina solvent inert to the reaction at a temperature between −20° C. and200° C., preferably between room temperature and 80° C., for 5 minutesto 72 hours.

Examples of the solvent inert to the reaction include water, aceticacid, hydrochloric acid, trifluoroacetic acid, trifluoromethanesulfonicacid, methanol, ethanol, propanol, THF, dioxane, ether,1,2-dimethoxyethane, benzene, toluene, xylene, DMF, DMA, NMP, pyridine,and the like. These solvents can be used alone or as a mixture thereof.Among these, preferred is water, acetic acid, or a combination thereof.

Examples of the reducing agent include iron(0), tin(0), tin(II)dichloride, tin(II) dichloride dihydrate, zinc, sodium hydrosulfite, andthe like. Among these, preferred is iron (0), or the like.

Step 3

Compound (I) can be produced from Compound (XIa-1) in the same manner asin Step 1 of Production Method 3.

Production Method 6

Among Compounds (I), an enantiomer of Compound (I) having asymmetry in—C(R³)(R⁶)(R⁷) can be obtained by subjecting Compound (I) obtained byProduction Methods 1 to 5 to chromatography using an optically activecolumn. Alternatively, the enantiomer can be obtained by subjectingCompound (VIIa-1) obtained by Production Method 2, Compound (IXa-1)obtained by Production Method 4, or Compound (XIIa-1) obtained byProduction Method 5 to chromatography using an optically active columnto produce the corresponding enantiomer, and subjecting the resultingenantiomer to the next step of each Production Method.

Further alternatively, the enantiomer can be obtained by using anenantiomer of Compound (VI) in Production Methods 1 to 5. The enantiomerof Compound (VI) can be obtained as a commercial product, or accordingto known methods (for example, WO 98/42643 and the like).

Isolation and purification of the products in the above respectiveProduction Methods can be performed by an appropriate combination ofmethods generally employed in organic synthesis, for example,filtration, extraction, washing, drying, concentration, crystallization,various types of chromatography, and the like. The intermediates can besubjected to the subsequent reaction without any particularpurification.

Some of Compounds (I) exist as isomers such as stereoisomers,regioisomers, geometric isomers, optical isomers (enantiomers), and thelike. All possible isomers and mixtures containing the isomers at anyratio are also included and used in the present invention.

A salt of Compound (I) can be obtained as follows. When Compound (I) isobtained in the form of a salt, the salt may be directly purified. WhenCompound (I) is obtained in a free form, the compound may be dissolvedor suspended in a suitable solvent, and then an acid, a base, or thelike may be added thereto for salt formation.

Compound (I) or a pharmaceutically acceptable salt thereof may exist inthe form of adducts with water or any of various solvents in some cases,and these adducts are also included and used in the present invention.

Specific examples of the compounds used in the present invention areshown in Table 1. However, the scope of the present invention is notlimited to these compounds. The compounds shown in Table 1 below are theones produced in the respective Examples described later.

In the following Table, Me and Pr represent methyl and propyl,respectively.

TABLE 1

Example Compound No. No. R¹ O—C(R³)(R⁶)(R⁷) 1 1

2 2

3 3

4 4

5 5

6 6

7 7

8 8

9 9

10 10

11 11

12 12

13 13

14 14

15 15

16 16

17 17

18 18

19 19

20 20

21 21

22 22

23 23

24 24

25 25

26 26

27 27

28 28

29 29

30 30

31 31

32 32

33 33

34 34

35 35

36

36 37

37 38

38 39

39 40

41

40 42

41 43

42 44

43 45

44 46

45 47

46 48

47 49

48 50

49 51

50 52

51 53

52 54

53 55

54 56

55 57

56 58

57 59

58 60

59 61

60 62

61 63

62 64

64A Of the two enantiomers of Compounds 64, the compound having longerretention time 64B Of the two enantiomers of Compounds 64, the compoundhaving shorter retention time 63 65

64 66

65 67

66 68

68A Of the two enantiomers of Compounds 68, the compound having aretention time of 16 minutes 68B Of the two enantiomers of Compounds 68,the compound having a retention time of 30 minutes 67 69

68 70

69 71

70 72

71 73

72 74

73 75 Of the two enantiomers of Compounds 32, the compound havingshorter retention time 76 Of the two enantiomers of Compounds 32, thecompound having longer retention time

Example Compound No. No. R⁹ 74 77 I 75 78

76 79

Next, pharmacological effects of Compound (I) will be described withreference to Test Examples.

Test Example 1: Inhibitory Activity on the Production of Kynurenine

This assay was performed by a modification of the method described in J.Biol. Chem., vol. 263, pp. 2041-2048 (1988). For culture of the humangastric cancer cell line KATO-III, RPMI 1640 (GIBCO, 11875) supplementedwith 10 vol % FBS (GIBCO, 10091-148, lot. 665285) was used. One μL of atest substance in a DMSO solution was diluted with 199 μL of the culturemedium and placed in wells of a 384-well plate (10 μL/well). Next, IFN-γ(Sigma, I-3265) was added to the culture medium to a concentration of31.25 ng/mL, and KATO-III cells were suspended at 50,000 cells/mL in theculture medium. Forty μL of the suspension was added to each well (2,000cells/well) and incubated under a 5% CO₂ atmosphere at 37° C. for 96hours. The final concentration of DMSO was limited to 0.1 vol % or lessso that DMSO itself may not affect the kynurenine concentration measuredby this assay. After the incubation, 10 μL of a 30 w/v % aqueoustrichloroacetic acid solution was added to each well, and incubation wasperformed at 65° C. for 30 minutes. The plate was centrifuged at 2,500×gfor 5 minutes and 15 μL of the supernatant in each well was transferredinto another 384-well plate. To the transferred supernatant, 15 μL of a2 w/v % solution of p-dimethylaminobenzaldehyde in acetic acid wasadded, incubation was performed at 65° C. for 20 minutes and theabsorbance was measured at 480 nm.

${{Inhibition}{rate}(\%)} = {\frac{\left( {{Control} - {Sample}} \right)}{\left( {{Con{trol}} - {Blank}} \right)} \times 100}$

Sample: the absorbance value of the well to which a DMSO solutioncontaining a test substance was added and in which the cells weretreated with IFN-γ.

Blank: the absorbance value of the well to which DMSO not containing atest substance was added and in which the cells were treated with IFN-γ.

Control: the absorbance value of the well to which DMSO not containing atest substance was added and in which the cells were not treated withIFN-γ.

The results showed that, for example, the inhibition rates of Compounds3, 4, 6 to 8, 11 to 17, 19, 21 to 33, 40 to 55, 64 to 79, 64A, 64B and68A at a concentration of 10 μmol/L were 80% or more.

That is, the results revealed that Compounds (I) of the presentinvention have an inhibitory activity on the production of kynurenine.

In this assay, expression of IDO in KATO-III cells is induced by IFN-γtreatment and kynurenine in the culture medium is quantified. Thekynurenine concentration in a culture medium is known to increase inproportion to the enzymatic activity of intracellular IDO (for example,J. Biol. Chem., vol. 263, pp. 2041-2048 (1988)). The compounds of thepresent invention showed an inhibitory effect on the production ofkynurenine. The production of kynurenine is known to be inhibited by IDOinhibitors (for example, J. Clin. Invest., vol. 117, No. 5, pp.1147-1154 (1988)), and thus it is speculated that Compounds (I) alsohave an inhibitory effect on IDO.

Compounds having an inhibitory effect on the production of kynurenineand/or on IDO are known to be useful as an antitumor agent, an anti-AIDSagent, an anti-AIDS dementia agent, an anti-Alzheimer's disease agent,an antidepressant, or the like (for example, J. Clin. Invest., vol. 117,pp. 1147-1154 (2007); J. Virol., vol. 81, pp. 11593-11603 (2007);Neuropathol. Appl. Neurobiol., vol. 31, pp. 395-404 (2005); Neurosci.Lett., vol. 187, pp. 9-12 (1995); and Neuropsychopharmacology, vol. 33,2341-2351 (2008)). Such compounds are known to also have animmunostimulatory activity (for example, Nat. Immunol., vol. 2, pp.64-68 (2001)). Therefore Compounds (I) of the present invention areuseful as an antitumor agent, an anti-AIDS agent, an anti-AIDS dementiaagent, an anti-Alzheimer's disease agent, an antidepressant, animmunostimulator, or the like.

Compound (I) or a pharmaceutically acceptable salt thereof can be usedas it is or in various forms of pharmaceuticals depending on itspharmacological effect, the purpose of administration, and the like. Apharmaceutical composition of the present invention can be usuallyproduced by homogeneously mixing an effective amount of Compound (I) ora pharmaceutically acceptable salt thereof as an active ingredient witha pharmaceutically acceptable carrier. The carrier can be in a widerange of forms depending on the dosage form suitable for administration.Preferably, the pharmaceutical composition is in a dosage unit formsuitable for oral administration or parenteral administration such asinjection, and the like.

For preparation of tablets, for example, excipients such as lactose andmannitol; disintegrants such as starch; lubricants such as magnesiumstearate; binders such as polyvinyl alcohol and hydroxypropylcellulose;surfactants such as sucrose fatty acid ester and sorbitol fatty acidester; and the like can be used in a usual manner. Preferably, 1 to 200mg of the active ingredient is contained per tablet.

For preparation of injections, water; saline; vegetable oils such asolive oil and peanut oil; solvents such as ethyl oleate and propyleneglycol; solubilizing agents such as sodium benzoate, sodium salicylateand urethane; tonicity agents such as salts and glucose; preservativessuch as phenol, cresol, p-hydroxybenzoic acid esters and chlorobutanol;anti-oxidants such as ascorbic acid and sodium pyrosulfite; and the likecan be used in a usual manner.

Compound (I) or a pharmaceutically acceptable salt thereof can beadministered orally or parenterally (examples: injections, and thelike). The effective dose and dose frequency vary depending on thedosage form, the age, body weight and condition of a patient, and thelike, but in general, the daily dose is preferably 0.01 to 100 mg/kg.

Subjects to which Compound (I) or a pharmaceutically acceptable saltthereof is administered are preferably patients with the above-describeddiseases involving the production of kynurenine. Among these, patientswith cancers (tumors), neurodegenerative diseases, infections, immunediseases, or the like are suitable, and patients with cancers (tumors)or the like are more suitable. These patients can be selected by a knowndiagnosis method. For prevention of the onset of these diseases, theabove compound can also be administered to mammals which may develop thediseases. Compound (I) or a pharmaceutically acceptable salt thereof ora composition containing said compound or salt thereof can beadministered orally or parenterally to humans and non-human mammals(examples: mice, rats, hamsters, guinea pigs, rabbits, cats, dogs, pigs,cows, horses, sheep, monkeys, and the like).

Hereinafter, the present invention will be illustrated in more detail byway of Examples and Reference Examples, but is not limited thereto.

Regarding a proton nuclear magnetic resonance spectrum (¹H-NMR),exchangeable hydrogens are not clearly observed in some compounds and onthe measurement conditions. The multiplicity of the signals is denotedby notations which are generally employed, and the symbol “br”represents an apparent broad signal.

The instrumental data of the compounds in the respective ReferenceExamples and Examples below were measured with the following devices.

¹H-NMR: JEOL JNM-EX270 (270 MHz) or JEOL JNM-AL300 (300 MHz) MS: JEOLSX-102AQQ (FAB method), JEOL JMS-DX303 (FAB method), Micromass Quattro(APCI method) or Micromass LCT (ESI, APCI method)

Unless otherwise noted, the symbol “%” regarding the concentration means“% by mass”, and the ratio of solvents means the volume ratio of thesolvents.

Each compound was named using ChemBioDraw ver. 11.0 (Cambridge soft).

Reference Example 1 N-(3-chloroquinoxalin-2-yl) propane-1-sulfonamide(Compound A1

In DMSO were dissolved 2,3-dichloroquinoxaline (5.00 g, 25.1 mmol) andpropane-1-sulfonamide (3.09 g, 25.1 mmol). Potassium carbonate (3.47 g,25.1 mmol) was added and the mixture was stirred at 150° C. for 1 hour.A 1% aqueous acetic acid solution was added to the reaction mixture andthe mixture was stirred at room temperature for 3 hours. The resultingsolid was separated by filtration, washed with water, and purified byslurrying in diisopropyl ether to give Compound A1 (6.01 g, 84% yield).

Reference Example 2 N-(3-chloroquinoxalin-2-yl) butane-1-sulfonamide(Compound A2

According to Reference Example 1, Compound A2 was obtained from2,3-dichloroquinoxaline and butane-1-sulfonamide.

Reference Example 3N-(3-chloroquinoxalin-2-yl)-2-methylpropane-1-sulfonamide (Compound A3

According to Reference Example 1, Compound A3 was obtained from2,3-dichloroquinoxaline and 2-methylpropane-1-sulfonamide.

Reference Example 4N-(3-chloroquinoxalin-2-yl)-1-cyclopropylmethanesulfonamide (Compound A4

According to Reference Example 1, Compound A4 was obtained from2,3-dichloroquinoxaline and 1-cyclopropyl methylsulfonamide.

Reference Example 5N-(3-chloroquinoxalin-2-yl)-N-((2-(trimethylsilyl)ethoxy)methyl)propane-1-sulfonamide(Compound A5

Compound A1 (1.22 g, 4.28 mmol) obtained in Reference Example 1 wasdissolved in dichloromethane (12.0 mL). Diisopropylethylamine (1.5 mL,8.6 mmol) and 2-(trimethylsilyl)ethoxymethyl chloride (1.10 mL, 6.40mmol) were added and the mixture was stirred at room temperature for 30minutes. Water was added to the reaction mixture. Extraction with ethylacetate, washing with saturated brine and drying over anhydrous sodiumsulfate were performed. After filtration, the solvent in the filtratewas evaporated under reduced pressure. The residue was purified bysilica gel column chromatography (hexane/ethyl acetate=5/1) to giveCompound A5 (1.68 g, 94% yield).

Reference Example 6N-(3-chloroquinoxalin-2-yl)-N-((2-(trimethylsilyl)ethoxy)methyl) butane1-sulfonamide (Compound A6

According to Reference Example 5, Compound A6 (1.08 g, 75% yield) wasobtained from Compound A2 (1.00 g, 3.34 mmol) obtained in ReferenceExample 2.

Reference Example 7N-(3-chloroquinoxalin-2-yl)-N-((2-(trimethylsilyl)ethoxy)methyl)-2-methylpropane-1-sulfonamide(Compound A7

According to Reference Example 5, Compound A7 (434 mg, 60%) was obtainedfrom Compound A3 (500 mg, 1.67 mmol) obtained in Reference Example 3.

Reference Example 8N-(3-chloroquinoxalin-2-yl)-1-cyclopropyl-N-((2-(trimethylsilyl)ethoxy)methyl)methanesulfonamide (Compound A8

According to Reference Example 5, Compound A8 (425 mg, 98%) was obtainedfrom Compound A4 (300 mg, 1.01 mmol) obtained in Reference Example 4.

Reference Example 9 2-chloro-3-((1-methylcyclopropyl)(pyridin-3-yl)methoxy) quinoxaline (Compound A9 Step 1

To toluene (12 mL) were added dropwise at −78° C. n-butyllithium (2.76mol/L solution in n-hexane, 4.14 mL, 11.4 mmol) and a solution of3-bromopyridine (1.00 mL, 10.4 mmol) in toluene (4.0 mL), and themixture was stirred at the same temperature for 30 minutes. THF (4.0 mL)was added to the resulting suspension. After stirring at −78° C. for 15minutes, methacrolein (1.03 mL, 12.5 mmol) was added, and the mixturewas stirred for 1 hour allowing the temperature to rise slowly to roomtemperature. A saturated aqueous ammonium chloride solution and waterwere added to the reaction mixture. Extraction with ethyl acetate,washing with saturated brine and drying over anhydrous sodium sulfatewere performed. After filtration, the solvent in the filtrate wasevaporated under reduced pressure. The residue was purified by silicagel column chromatography (hexane/ethyl acetate=3/7) to give2-methyl-1-(pyridin-3-yl)prop-2-en-1-ol (1.08 g, 70% yield).

Step 2

In dichloromethane (40.0 mL) was dissolved2-methyl-1-(pyridin-3-yl)prop-2-en-1-ol (1.04 g, 6.95 mmol) obtained inStep 1. Diethylzinc (1.09 mol/L solution in n-hexane, 31.9 mL, 34.7mmol) and diiodomethane (2.80 mL, 34.7 mmol) were added dropwise at −10°C. and the mixture was stirred at 0° C. for 2.5 hours. A saturatedaqueous ammonium chloride solution and water were added to the reactionmixture. Extraction with ethyl acetate, washing with saturated brine anddrying over anhydrous sodium sulfate were performed. After filtration,the solvent in the filtrate was evaporated under reduced pressure. Theresidue was purified by silica gel column chromatography (hexane/ethylacetate=3/7) to give (1-methylcyclopropyl) (pyridin-3-yl)methanol (888mg, 78% yield).

Step 3

In THF (5.0 mL) were dissolved (1-methylcyclopropyl)(pyridin-3-yl)methanol (130 mg, 0.796 mmol) obtained in Step 2 and2,3-dichloroquinoxaline (190 mg, 0.956 mmol). To the mixture was added60% sodium hydride (in oil, 38.2 mg, 0.956 mmol) and the mixture wasstirred at 50° C. for 1.5 hours. A saturated aqueous ammonium chloridesolution and water were added to the reaction mixture. Extraction withethyl acetate, washing with saturated brine and drying over anhydroussodium sulfate were performed. After filtration, the solvent in thefiltrate was evaporated under reduced pressure. The residue was purifiedby silica gel column chromatography (hexane/ethyl acetate=17/3) to giveCompound A9 (147 mg, 57% yield).

Reference Example 102-chloro-3-(2,2,2-trifluoro-1-(4-(methylsulfonyl)phenyl)ethoxy)quinoxaline (Compound A10 Step 1

In THF (10.0 mL) was dissolved 4-(methylsulfonyl)benzaldehyde (500 mg,2.71 mmol). To the solution were added (trifluoromethyl)trimethylsilane(0.602 mL, 4.07 mmol) and tetrabutylammonium fluoride (1.0 mol/Lsolution in THF, 0.136 mL, 0.136 mmol), and the mixture was stirred atroom temperature for 1 hour. To the mixture was added 1 mol/Lhydrochloric acid and the mixture was stirred at room temperature for 5minutes. A saturated aqueous sodium bicarbonate solution was added tothe reaction mixture. Extraction with ethyl acetate, washing withsaturated brine and drying over anhydrous sodium sulfate were performed.After filtration, the solvent in the filtrate was evaporated underreduced pressure. The residue was purified by silica gel columnchromatography (hexane/ethyl acetate=1/1) to give2,2,2-trifluoro-1-(4-(methylsulfonyl)phenyl) ethanol (454 mg, 66%yield).

Step 2

According to Step 3 of Reference Example 9, Compound A10 (244 mg, 32%yield) was obtained from 2,2,2-trifluoro-1-(4-(methylsulfonyl)phenyl)ethanol (454 mg, 1.78 mmol) obtained in Step 1.

Reference Example 115-(1-(3-chloroquinoxalin-2-yloxy)-2,2,2-trifluoroethyl) picolinonitrile(Compound A11 Step 1

In toluene (100 mL) were suspended 6-bromo-3-pyridinecarboxyaldehyde(1.03 g, 5.54 mmol), ethylene glycol (370 μL, 6.65 mmol) and Amberlyst15 (200 mg). The suspension was refluxed under a nitrogen atmosphere for12 hours, during which produced water was removed with a Dean-Starktrap. After filtration of the reaction mixture, the filtrate wasconcentrated. The residue was purified by silica gel columnchromatography (hexane/ethyl acetate=7/3) to give2-bromo-5-(1,3-dioxolan-2-yl)pyridine (895 mg, 70% yield).

Step 2

In DMF (30 mL) were dissolved 2-bromo-5-(1,3-dioxolan-2-yl)pyridine (895mg, 3.89 mmol) obtained in Step 1, zinc cyanide (1.14 g, 5.83 mmol) andtetrakis(triphenylphosphine) palladium (899 mg, 0.778 mmol) and themixture was stirred under a nitrogen atmosphere at 80° C. for 12 hours.The reaction mixture was concentrated and water was added. Extractionwith ethyl acetate, washing with saturated brine and drying overanhydrous sodium sulfate were performed. After filtration, the solventin the filtrate was evaporated under reduced pressure. The residue waspurified by silica gel column chromatography (hexane/ethyl acetate=7/3)to give 5-(1,3-dioxolan-2-yl)picolinonitrile (506 mg, 74% yield).

Step 3

In THF (5.0 mL) was dissolved 5-(1,3-dioxolan-2-yl)picolinonitrile (478mg, 2.71 mmol) obtained in Step 2, and 1 mol/L hydrochloric acid (5.0mL) was added under a nitrogen atmosphere at room temperature. Themixture was stirred at the same temperature for 16 hours and furtherstirred at 50° C. for 13 hours. The reaction mixture was neutralizedwith a saturated aqueous sodium bicarbonate solution. Extraction withethyl acetate, washing with saturated brine and drying over anhydroussodium sulfate were performed. After filtration, the solvent in thefiltrate was evaporated under reduced pressure to give5-formylpicolinonitrile (364 mg, 100% yield).

Step 4

According to Step 1 of Reference Example 10,5-(2,2,2-trifluoro-1-hydroxyethyl)picolinonitrile (455 mg, 82% yield)was obtained from 5-formylpicolinonitrile (364 mg, 2.76 mmol) obtainedin Step 3.

Step 5

According to Step 3 of Reference Example 9, Compound A11 (292 mg, 38%yield) was obtained from5-(2,2,2-trifluoro-1-hydroxyethyl)picolinonitrile (424 mg, 2.10 mmol)obtained in Step 3.

Reference Example 122-(5-(1-(3-chloroquinoxalin-2-yloxy)-2,2,2-trifluoroethyl)pyridin-2-yl)propan-2-ol (Compound A12 Step 1

According to Step 1 of Reference Example 10,1-(6-bromopyridin-3-yl)-2,2,2-trifluoroethanol (3.69 g, 90% yield) wasobtained from 6-bromonicotinaldehyde (3.00 g, 16.1 mmol).

Step 2

In n-propanol (3.0 mL) and DMF (3.0 mL) was dissolved1-(6-bromopyridin-3-yl)-2,2,2-trifluoroethanol (300 mg, 1.17 mmol)obtained in Step 1. To the solution were added[1,1′-bis(diphenylphosphino) ferrocene]palladium (II)chloride-dichloromethane complex (85.6 mg, 0.117 mmol),1,1′-bis(diphenylphosphino) ferrocene (130 mg, 0.234 mmol) andtriethylamine (1.63 mL, 11.7 mL). The mixture was stirred under a carbonmonoxide atmosphere at 80° C. for 18 hours. The solvent was evaporatedunder reduced pressure and water was added. Extraction with ethylacetate, washing with saturated brine and drying over anhydrous sodiumsulfate were performed. After filtration, the solvent in the filtratewas evaporated under reduced pressure. The residue was purified bysilica gel column chromatography (hexane/ethyl acetate=1/1) and furtherpurified by preparative thin-layer chromatography (hexane/ethylacetate=1/1) to give propyl 5-(2,2,2-trifluoro-1-hydroxyethyl)picolinate(284 mg, 92% yield).

Step 3

In THF (5.0 mL) was dissolved propyl5-(2,2,2-trifluoro-1-hydroxyethyl)picolinate (284 mg, 1.08 mmol)obtained in Step 2. Methylmagnesium bromide (0.93 mol/L solution in THF,5.80 mL, 5.39 mmol) was added dropwise at −78° C., and the mixture wasstirred for 1 hour allowing the temperature to rise slowly to roomtemperature. A saturated aqueous ammonium chloride solution and waterwere added to the reaction mixture. Extraction with ethyl acetate,washing with saturated brine and drying over anhydrous sodium sulfatewere performed. After filtration, the solvent in the filtrate wasevaporated under reduced pressure. The residue was purified by silicagel column chromatography (hexane/ethyl acetate=1/1) to give2-(5-(2,2,2-trifluoro-1-hydroxyethyl)pyridin-2-yl)propan-2-ol (222 mg,87% yield).

Step 4

According to Step 3 of Reference Example 9, Compound A12 (179 mg, 73%yield) was obtained from2-(5-(2,2,2-trifluoro-1-hydroxyethyl)pyridin-2-yl)propan-2-ol (162 mg,0.615 mmol) obtained in Step 3.

Reference Example 132-chloro-3-(2,2,2-trifluoro-1-(5-(methylsulfonyl)pyridin-3-yl)ethoxy)quinoxaline(Compound A13 Step 1

In diethyl ether (42.0 mL) was dissolved 3,5-dibromopyridine (1.00 g,4.22 mmol). n-Butyllithium (2.76 mol/L solution in n-hexane, 1.61 mL,4.43 mmol) was added dropwise at −78° C., and the mixture was stirred atthe same temperature for 30 minutes. Further, DMF (0.98 mL, 12.7 mmol)was added and the mixture was stirred for 3 hours allowing thetemperature to rise slowly to room temperature. A saturated aqueousammonium chloride solution and water were added to the reaction mixture.Extraction with ethyl acetate, washing with saturated brine and dryingover anhydrous sodium sulfate were performed. After filtration, thesolvent in the filtrate was evaporated under reduced pressure. Theresidue was purified by silica gel column chromatography (hexane/ethylacetate=7/3) to give 5-bromonicotinaldehyde (314 mg, 40%).

Step 2

According to Step 1 of Reference Example 10,1-(5-bromopyridin-3-yl)-2,2,2-trifluoroethanol (390 mg, 90% yield) wasobtained from 5-bromonicotinaldehyde (314 mg, 1.69 mmol) obtained inStep 1.

Step 3

In pyridine (2.0 mL) was dissolved1-(5-bromopyridin-3-yl)-2,2,2-trifluoroethanol (390 mg, 1.52 mmol)obtained in Step 2. Acetic anhydride (2.0 mL) was added and the mixturewas stirred at room temperature for 18 hours. The solvent was evaporatedunder reduced pressure and a saturated aqueous sodium bicarbonatesolution and water were added. Extraction with ethyl acetate, washingwith saturated brine and drying over anhydrous sodium sulfate wereperformed. After filtration, the solvent in the filtrate was evaporatedunder reduced pressure. The residue was purified by silica gel columnchromatography (hexane/ethyl acetate=1/1) and further purified bypreparative thin-layer chromatography (hexane/ethyl acetate=4/1) to give1-(5-bromopyridin-3-yl)-2,2,2-trifluoroethyl acetate (429 mg, 95%yield).

Step 4

In DMSO (3.0 mL) was dissolved1-(5-bromopyridin-3-yl)-2,2,2-trifluoroethyl acetate (429 mg, 1.44 mmol)obtained in Step 3. To the solution were added sodium methanesulfinate(176 mg, 1.73 mmol), copper iodide (I) (41.1 mg, 0.216 mmol), L-proline(49.7 mg, 0.432 mmol) and sodium bicarbonate (36.3 mg, 0.432 mg) and themixture was stirred at 95° C. for 72 hours. Water was added to thereaction mixture. Extraction with ethyl acetate, washing with saturatedbrine and drying over anhydrous sodium sulfate were performed. Afterfiltration, the solvent in the filtrate was evaporated under reducedpressure and the residue was dissolved in methanol (10.0 mL). Potassiumcarbonate (597 mg, 4.32 mmol) was added and the mixture was stirred atroom temperature for 1 hour. The solvent was evaporated under reducedpressure and water was added. Extraction with ethyl acetate, washingwith saturated brine and drying over anhydrous sodium sulfate wereperformed. After filtration, the solvent in the filtrate was evaporatedunder reduced pressure. The residue was purified by silica gel columnchromatography (hexane/ethyl acetate=3/7) to give2,2,2-trifluoro-1-(5-(methylsulfonyl)pyridin-3-yl)ethanol (61.4 mg, 17%yield).

Step 5

According to Step 3 of Reference Example 9, Compound A13 (69.1 mg, 69%yield) was obtained from2,2,2-trifluoro-1-(5-(methylsulfonyl)pyridin-3-yl)ethanol (61.4 mg,0.241 mmol) obtained in Step 4.

Reference Example 14 2-methyl-1-(pyridin-3-yl)propane-1,2-diol (CompoundA14 Step 1

Nicotinaldehyde (1.00 mL, 9.66 mmol) was dissolved in dichloromethane(20 mL). To the solution were added trimethylsilyl cyanide (0.129 mL,9.66 mmol) and triphenylmethylphosphonium iodide (437 mg, 0.966 mmol)and the mixture was stirred at room temperature for 18 hours. Water wasadded to the reaction mixture. Extraction with dichloromethane anddrying over anhydrous sodium sulfate were performed. After filtration,the solvent in the filtrate was evaporated under reduced pressure. Theresidue was purified by silica gel column chromatography (hexane/ethylacetate=7/3) to give 2-(pyridin-3-yl)-2-(trimethylsilyloxy) acetonitrile(650 mg, 33%).

Step 2

A 10% hydrogen chloride/methanol solution (6.5 mL) was added to2-(pyridin-3-yl)-2-(trimethylsilyloxy)acetonitrile (650 mg, 3.15 mmol)obtained in Step 1 and the mixture was stirred at room temperature for 4hours. The solvent was evaporated under reduced pressure and a saturatedaqueous sodium bicarbonate solution was added. Extraction with ethylacetate, washing with saturated brine and drying over anhydrous sodiumsulfate were performed. After filtration, the solvent in the filtratewas evaporated under reduced pressure. The residue was purified bysilica gel column chromatography (ethyl acetate: 100%) to give methyl2-hydroxy-2-(pyridin-3-yl)acetate (415 mg, 79% yield).

Step 3

Methyl 2-hydroxy-2-(pyridin-3-yl)acetate (415 mg, 2.48 mmol) obtained inStep 2 was dissolved in THF (3.0 mL). Methylmagnesium bromide (0.87mol/L solution in THF, 14.3 mL, 12.4 mmol) was added dropwise at 0° C.and the mixture was stirred for 2 hours allowing the temperature to riseslowly to room temperature. A saturated aqueous ammonium chloridesolution and water were added to the reaction mixture. Extraction withethyl acetate, washing with saturated brine and drying over anhydroussodium sulfate were performed. After filtration, the solvent in thefiltrate was evaporated under reduced pressure. The residue was purifiedby silica gel column chromatography (hexane/ethyl acetate=9/1) to giveCompound A14 (206 mg, 50% yield).

Reference Example 15 2,2-dimethyl-1-(pyridin-3-yl)propan-1-ol (CompoundA15

According to Step 1 of Reference Example 9, Compound A15 (1.58 mg, 92%yield) was obtained from 3-bromopyridine (1.00 mL, 10.4 mmol) andpivalaldehyde (1.36 mL, 12.5 mmol).

Reference Example 16 1-cyclopropyl-1-(pyridin-3-yl)methanol (CompoundA16

According to Step 1 of Reference Example 9, Compound A16 (1.25 mg, 81%yield) was obtained from 3-bromopyridine (1.00 mL, 10.4 mmol) andcyclopropanecarbaldehyde (0.934 mL, 12.5 mmol).

Reference Example 17 2-fluoro-2-methyl-1-(pyridin-3-yl)propan-1-ol(Compound A17 Step 1

According to Step 1 of Reference Example 9,2-methyl-1-(pyridin-3-yl)propan-1-ol (2.43 g, 52% yield) was obtainedfrom 3-bromopyridine (3.00 mL, 31.1 mmol) and isobutyraldehyde (3.41 mL,37.3 mmol).

Step 2

In dichloromethane (60.0 mL) was dissolved2-methyl-1-(pyridin-3-yl)propan-1-ol (2.16 g, 14.3 mmol) obtained inStep 1. Manganese dioxide (107 g) was added and the mixture was stirredat room temperature for 7 hours. After the reaction mixture was filteredthrough Celite, the solvent in the filtrate was evaporated under reducedpressure. The residue was purified by silica gel column chromatography(hexane/ethyl acetate=1/1) to give 2-methyl-1-(pyridin-3-yl)propan-1-one(1.72 g, 81% yield).

Step 3

A solution of 2-methyl-1-(pyridin-3-yl)propan-1-one (1.72 g, 11.5 mmol)obtained in Step 2 in THF (20 mL) was slowly added dropwise to lithiumbis(trimethylsilyl)amide (1.0 mol/L solution in THF, 13.8 mL, 13.8 mmol)at −78° C. and the mixture was stirred at the same temperature for 30minutes. Further, N-fluorobenzenesulfonimide (4.36 g, 13.8 mmol) wasadded and the mixture was stirred for 1.5 hours allowing the temperatureto rise slowly to room temperature. A saturated aqueous ammoniumchloride solution and water were added to the reaction mixture.Extraction with ethyl acetate, washing with saturated brine and dryingover anhydrous sodium sulfate were performed. After filtration, thesolvent in the filtrate was evaporated under reduced pressure. Theresidue was purified by silica gel column chromatography (hexane/ethylacetate=4/1) to give 2-fluoro-2-methyl-1-(pyridin-3-yl)propan-1-one(1.73 g, 89% yield).

Step 4

In methanol (30.0 mL) was dissolved2-fluoro-2-methyl-1-(pyridin-3-yl)propan-1-one (1.73 g, 10.3 mmol)obtained in Step 3. Sodium borohydride (584 mg, 15.4 mmol) was added andthe mixture was stirred at 0° C. for 30 minutes. The solvent wasevaporated under reduced pressure and water was added. Extraction withethyl acetate, washing with saturated brine and drying over anhydroussodium sulfate were performed. After filtration, the solvent in thefiltrate was evaporated under reduced pressure. The residue was purifiedby silica gel column chromatography (hexane/ethyl acetate=1/1) andfurther purified by preparative thin-layer chromatography (hexane/ethylacetate=3/7) to give Compound A17 (1.54 g, 89% yield).

Reference Example 18 1-(pyridin-3-yl)pentan-1-ol (Compound A18

Nicotinaldehyde (0.500 mL, 4.83 mmol) was dissolved in THF (7.0 mL).n-Butyllithium (2.76 mol/L solution in n-hexane, 2.63 mL, 7.25 mmol) wasadded at −78° C. and the mixture was stirred at the same temperature for10 minutes. A saturated aqueous ammonium chloride solution and waterwere added to the reaction mixture. Extraction with ethyl acetate,washing with saturated brine and drying over anhydrous sodium sulfatewere performed. After filtration, the solvent in the filtrate wasevaporated under reduced pressure. The residue was purified by silicagel column chromatography (hexane/ethyl acetate=4/1) to give CompoundA18 (597 mg, 75% yield).

Reference Example 19 1-(pyridin-3-yl)propan-1-ol (Compound A19

A solution of nicotinaldehyde (0.200 mL, 0.12 mmol) in THF (2.0 mL) wasslowly added to ethylmagnesium bromide (1.0 mol/L solution in THF, 3.18mL, 3.18 mmol) at 0° C. The mixture was stirred at the same temperaturefor 1 hour and a saturated aqueous ammonium chloride solution was addedto the reaction mixture. Extraction with ethyl acetate, washing withsaturated brine and drying over anhydrous sodium sulfate were performed.After filtration, the solvent in the filtrate was evaporated underreduced pressure. The residue was purified by silica gel columnchromatography (chloroform/methanol=9/1) to give Compound A19 (194 mg,67% yield).

Reference Example 20 2,2-difluoro-1-(pyridin-3-yl)ethanol (Compound A20Step 1

To toluene (7.0 mL) were added dropwise at −78° C. n-butyllithium (2.76mol/L solution in n-hexane, 2.60 mL, 7.19 mmol) and a solution of3-bromopyridine (1.00 mL, 10.4 mmol) in toluene (2.5 mL), and themixture was stirred at the same temperature for 30 minutes. THF (4.0 mL)was added to the resulting suspension and the mixture was stirred at−78° C. for minutes. To the mixture was added2,2-difluoro-N-methoxy-N-methylacetamide (1.00 g, 7.19 mmol) and themixture was stirred for 3 hours allowing the temperature to rise slowlyto room temperature. A saturated aqueous ammonium chloride solution andwater were added to the reaction mixture. Extraction with ethyl acetate,washing with saturated brine and drying over anhydrous sodium sulfatewere performed. After filtration, the solvent in the filtrate wasevaporated under reduced pressure. The residue was purified by silicagel column chromatography (hexane/ethyl acetate=3/7) to give2,2-difluoro-1-(pyridin-3-yl)ethanone (868 mg, 91% yield).

Step 2

According to Step 4 of Reference Example 17, Compound A20 (724 mg, 83%yield) was obtained from 2,2-difluoro-1-(pyridin-3-yl)ethanone (864 mg,5.50 mmol) obtained in Step 1.

Reference Example 21 1-(pyridin-3-yl)ethanol (Compound A21

According to Step 4 of Reference Example 17, Compound A21 (724 mg, 83%yield) was obtained from 1-(pyridin-3-yl)ethanone (0.500 mL, 4.56 mmol).

Reference Example 22 1-(pyridin-3-yl)butan-1-ol (Compound A22

According to Step 1 of Reference Example 9, Compound A22 (403 mg, 27%yield) was obtained from 3-bromopyridine (1.00 mL, 10.4 mmol) andn-butyraldehyde (1.13 mL, 12.5 mmol).

Reference Example 23 Phenyl(pyridin-3-yl)methanol (Compound A23

According to Step 4 of Reference Example 17, Compound A23 (425 mg, 84%yield) was obtained from phenyl(pyridin-3-yl)methanone (0.500 mL, 2.73mmol).

Reference Example 242,2,2-trifluoro-1-(imidazo[1,2-a]pyridin-6-yl)ethanol (Compound A24

According to Step 1 of Reference Example 10, Compound A24 (224 mg, 59%yield) was obtained from imidazo[1,2-a]pyridine-6-carbaldehyde (258 mg,1.77 mmol).

Reference Example 25 2,2,2-trifluoro-1-(6-methylpyridin-3-yl)ethanol(Compound A25

According to Step 1 of Reference Example 10, Compound A25 (2.25 g, 83%yield) was obtained from 6-methylnicotinaldehyde (1.72 g, 14.2 mmol).

Reference Example 262,2,2-trifluoro-1-(6-(1-methyl-1H-pyrazol-4-yl)pyridin-3-yl)ethanol(Compound A26

In 1,4-dioxane (2.0 mL) was dissolved1-(6-bromopyridin-3-yl)-2,2,2-trifluoroethanol (98.6 mg, 0.385 mmol). Tothe solution were added1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole(120 mg, 0.578 mmol), cesium carbonate (188 mg, 0.578 mmol),tris(dibenzylideneacetone)dipalladium (5.3 mg, 0.0058 mmol),tricyclohexylphosphine (3.9 mg, 0.0139 mmol) and water (0.2 mL), and themixture was stirred at 80° C. for 2 hours. Water was added to thereaction mixture. Extraction with ethyl acetate, washing with saturatedbrine and drying over anhydrous sodium sulfate were performed. Afterfiltration, the solvent in the filtrate was evaporated under reducedpressure. The residue was purified by silica gel column chromatography(chloroform/methanol=19/1) to give Compound A26 (94.5 mg, 95% yield).

Reference Example 27 2,2,2-trifluoro-1-(6-(methylthio)pyridin-3-yl)ethanol (Compound A27 Step 1

In DMF (5.0 mL) was dissolved 6-chloronicotinaldehyde (300 mg, 2.12mmol). Sodium thiomethoxide (178 mg, 2.54 mmol) was added and themixture was stirred at room temperature for 2 hours. Water was added tothe reaction mixture. Extraction with ethyl acetate, washing withsaturated brine and drying over anhydrous sodium sulfate were performed.After filtration, the solvent in the filtrate was evaporated underreduced pressure. The residue was purified by silica gel columnchromatography (hexane/ethyl acetate=4/1) to give6-(methylthio)nicotinaldehyde (239 mg, 74%).

Step 2

According to Step 1 of Reference Example 10, Compound A27 (326 mg, 94%yield) was obtained from 6-(methylthio)nicotinaldehyde (238 mg, 1.55mmol) obtained in Step 1.

Reference Example 28 2,2,2-trifluoro-1-(pyridin-4-yl)ethanol (CompoundA28

According to Step 1 of Reference Example 10, Compound A28 (1.68 g, 94%)was obtained from isonicotinaldehyde (1.22 g, 4.28 mmol).

ESIMS m/z: 178 (M+H)⁺.

Reference Example 291-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-2,2,2-trifluoroethanol (CompoundA29

According to Step 1 of Reference Example 10, Compound A29 (639 mg, 89%yield) was obtained from 2,3-dihydrobenzo[b][1,4]dioxin-6-carbaldehyde(503 mg, 3.06 mmol).

Reference Example 302,2,2-trifluoro-1-(2-methylimidazo[1,2-a]pyridin-7-yl) ethanol (CompoundA30 Step 1

Compound A28 (1.00 g, 5.65 mmol) obtained in Reference Example 28 wasdissolved in acetic anhydride (5.0 mL) and pyridine (5 mL) and themixture was stirred at room temperature for 1 hour. The solvent wasevaporated under reduced pressure. The residue was dissolved indichloromethane (10.0 mL) and 65% meta-chloroperbenzoic acid (650 mg,2.82 mmol) was added at 0° C. The mixture was stirred at roomtemperature for 3 hours and a 20% aqueous sodium thiosulfate solutionwas added to the reaction mixture. Extraction with chloroform and dryingover anhydrous sodium sulfate were performed. After filtration, thesolvent in the filtrate was evaporated under reduced pressure. Theresidue was purified by silica gel column chromatography(chloroform/methanol=10/1) to give4-(1-acetoxy-2,2,2-trifluoroethyl)pyridine 1-oxide (1.09 g, 82% yield).

Step 2

According to Example 43, 1-(2-aminopyridin-4-yl)-2,2,2-trifluoroethylacetate (53.2 mg, 27% yield) was obtained from4-(1-acetoxy-2,2,2-trifluoroethyl)pyridine 1-oxide (197 mg, 0.838 mmol)obtained in Step 1.

Step 3

In n-butanol (2 mL) was dissolved1-(2-aminopyridin-4-yl)-2,2,2-trifluoroethyl acetate (53.2 mg, 0.227mmol) obtained in Step 2. Bromoacetone (0.042 mL, 0.45 mmol) was addedand the mixture was stirred at 130° C. for 24 hours. A saturated aqueoussodium bicarbonate solution and water were added to the reactionmixture. Extraction with ethyl acetate and drying over anhydrous sodiumsulfate were performed. After filtration, the solvent in the filtratewas evaporated under reduced pressure and the residue was dissolved inmethanol (2.0 mL). Potassium carbonate (31.4 mg, 0.227 mmol) was addedand the mixture was stirred at room temperature for 18 hours. Asaturated aqueous ammonium chloride solution was added to the reactionmixture. Extraction with ethyl acetate and drying over anhydrous sodiumsulfate were performed. After filtration, the solvent in the filtratewas evaporated under reduced pressure. The residue was purified bysilica gel column chromatography (chloroform/methanol=5/1) to giveCompound A30 (20.7 mg, 40% yield).

ESIMS m/z: 218 (M+H)⁺.

Reference Example 312,2,2-trifluoro-1-(2-(methylthio)pyrimidin-5-yl)ethanol (Compound A31

According to Step 1 of Reference Example 10, Compound A31 (245 mg, 84%yield) was obtained from 2-(methylthio)pyrimidine-5-carbaldehyde (200mg, 1.30 mmol).

ESIMS m/z: 225 (M+H)⁺.

Reference Example 32 1-(benzo[d][1,3]dioxol-5-yl)-2,2,2-trifluoroethanol(Compound A32

According to Step 1 of Reference Example 10, Compound A32 (614 mg, 82%yield) was obtained from benzo[d][1,3]dioxole-5-carbaldehyde (510 mg,3.40 mmol).

Reference Example 33 tert-butyl6-(2,2,2-trifluoro-1-hydroxyethyl)-1H-indazole-1-carboxylate (CompoundA33 Step 1

In dichloromethane (3.0 mL) was suspended 1H-indazole-6-carbaldehyde(231 mg, 1.75 mmol). Di-tert-butyl dicarbonate (0.45 mL, 1.9 mmol) and4-dimethylaminopyridine (18.4 mg, 0.151 mmol) were added and the mixturewas stirred at room temperature for 30 minutes. The solvent wasevaporated under reduced pressure. The residue was purified by silicagel column chromatography (hexane/ethyl acetate=1/1) to give tert-butyl6-formyl-1H-indazole-1-carboxylate (389 mg, 90% yield).

Step 2

According to Step 1 of Reference Example 10, Compound A33 (278 mg, 56%yield) was obtained from tert-butyl 6-formyl-1H-indazole-1-carboxylate(389 mg, 1.58 mmol) obtained in Step 1.

ESIMS m/z: 317 (M+H)⁺.

Reference Example 34 tert-butyl5-(2,2,2-trifluoro-1-hydroxyethyl)-1H-indazole-1-carboxylate (CompoundA34

According to Reference Example 33, Compound A34 (235 mg, 2 steps 56%yield) was obtained from tert-butyl 5-formyl-1H-indazole-1-carboxylate(193 mg, 1.32 mmol).

ESIMS m/z: 317 (M+H)⁺.

Reference Example 35 2,2,2-trifluoro-1-(pyrimidin-5-yl)ethanol (CompoundA35

According to Step 1 of Reference Example 10, Compound A35 (342 mg, 69%yield) was obtained from pyrimidine-5-carbaldehyde (300 mg, 2.46 mmol).

ESIMS m/z: 179 (M+H)⁺.

Reference Example 36 2,2,2-trifluoro-1-(2-methylpyrimidin-5-yl)ethanol(Compound A36

According to Step 1 of Reference Example 10, Compound A36 (672 mg, 85%yield) was obtained from 2-methylpyrimidine-5-carbaldehyde (500 mg, 4.09mmol).

ESIMS m/z: 193 (M+H)⁺.

Reference Example 37N-(3-chloroquinoxalin-2-yl)-2-methoxy-N-((2-(trimethylsilyl)ethoxy)methyl)ethanesulfonamide(Compound A37) Step 1

In water (16 mL) was suspended 1-bromo-2-methoxyethane (2.00 mL, 21.3mmol). Sodium sulfite (2.95 g, 23.4 mmol) was added and the mixture wasrefluxed for 24 hours. The solvent in the reaction mixture wasevaporated under reduced pressure and the residue was purified byslurrying in chloroform to give a white solid (6.11 g). To the whitesolid were added thionyl chloride (15.5 mL, 213 mmol) and DMF (0.082 mL,1.06 mmol) and the mixture was stirred at 100° C. for 3 hours. Thesolvent in the reaction mixture was evaporated under reduced pressure.Chloroform was added, insoluble substance was filtered off, and thesolvent in the filtrate was evaporated under reduced pressure. A 25%aqueous ammonia solution (10 mL) was added to the resulting residue andthe mixture was stirred at room temperature for 3 hours. The solvent inthe reaction mixture was evaporated under reduced pressure. Chloroformwas added, insoluble substance was filtered off, and the solvent in thefiltrate was evaporated under reduced pressure. The residue was purifiedby silica gel column chromatography (hexane/ethyl acetate=3/7) to give2-methoxyethanesulfonamide (1.36 g, 46% yield).

Step 2

According to Reference Example 1,N-(3-chloroquinoxalin-2-yl)-2-methoxyethanesulfonamide (537 mg, 80%yield) was obtained from 2-methoxyethanesulfonamide (308 mg, 2.21 mmol)obtained in Step 1.

Step 3

According to Reference Example 5, Compound A37 (1.38 g, 96% yield) wasobtained from N-(3-chloroquinoxalin-2-yl)-2-methoxyethanesulfonamide(1.00 g, 3.31 mmol) obtained in Step 2.

Reference Example 383-(5-(1-(3-chloroquinoxalin-2-yloxy)-2,2,2-trifluoroethyl)pyridin-2-yl)-5-methyl-1,2,4-oxadiazole (Compound A38 Step 1

According to Step 2 of Reference Example 11,5-(diethoxymethyl)picolinonitrile (884 mg, 59% yield) was obtained from2-bromo-5-(diethoxymethyl)pyridine (1.89 g, 7.27 mmol) obtained in Step1 of Reference Example 43.

Step 2

In ethanol (5 mL) was dissolved 5-(diethoxymethyl)picolinonitrile (230mg, 1.12 mmol) obtained in Step 1. A 50% aqueous hydroxylamine solution(0.368 g, 5.58 mmol) was added and the mixture was stirred at roomtemperature for 1 hour. Water was added to the reaction mixture.Extraction with ethyl acetate, washing with saturated brine and dryingover anhydrous sodium sulfate were performed. After filtration, thesolvent in the filtrate was evaporated under reduced pressure. Theresulting white solid was dissolved in pyridine (5 mL). Acetyl chloride(0.396 mL, 5.58 mmol) was added and the mixture was stirred at 100° C.for 12 hours. The solvent in the reaction mixture was evaporated underreduced pressure and water was added. Extraction with ethyl acetate,washing with saturated brine and drying over anhydrous sodium sulfatewere performed. After filtration, the solvent in the filtrate wasevaporated under reduced pressure. The residue was purified by silicagel column chromatography (hexane/ethyl acetate=3/7) to give6-(5-methyl-1,2,4-oxadiazol-3-yl)nicotinaldehyde (200 mg, 95% yield).

Step 3

According to Step 1 of Reference Example 10,2,2,2-trifluoro-1-(6-(5-methyl-1,2,4-oxadiazol-3-yl)pyridin-3-yl)ethanol (189 mg, 69% yield) was obtained from6-(5-methyl-1,2,4-oxadiazol-3-yl)nicotinaldehyde (200 mg, 1.05 mmol)obtained in Step 2.

Step 4

According to Step 3 of Reference Example 9, Compound A38 (146 mg, 48%yield) was obtained from2,2,2-trifluoro-1-(6-(5-methyl-1,2,4-oxadiazol-3-yl)pyridin-3-yl)ethanol (189 mg, 0.729 mg) obtained in Step 3.

Reference Example 392-chloro-3-(2,2,2-trifluoro-1-(6-(1-methyl-1H-pyrazol-5-yl)pyridin-3-yl)ethoxy)quinoxaline (Compound A39 Step 1

According to Reference Example 26,2,2,2-trifluoro-1-(6-(1-methyl-1H-pyrazol-5-yl)pyridin-3-yl)ethanol (777mg, 77% yield) was obtained from1-(6-bromopyridin-3-yl)-2,2,2-trifluoroethanol (1.00 g, 3.91 mmol) and1-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole(1.12 mg, 5.86 mmol).

Step 2

According to Step 3 of Reference Example 9, Compound A39 (144 mg, 88%yield) was obtained from2,2,2-trifluoro-1-(6-(1-methyl-1H-pyrazol-5-yl)pyridin-3-yl)ethanol (100mg, 0.389 mg) obtained in Step 1.

Reference Example 402-chloro-3-(2,2,2-trifluoro-1-(6-(2-methyl-2H-1,2,3-triazol-4-yl)pyridin-3-yl)ethoxy)quinoxaline(Compound A40

According to Step 3 of Reference Example 9, Compound A40 (528 mg, 80%yield) was obtained from Compound A43 (406 mg, 1.57 mmol) in ReferenceExample 43.

Reference Example 412-chloro-3-(2,2,2-trifluoro-1-(6-(2-methyl-1H-imidazol-1-yl)pyridin-3-yl)ethoxy)quinoxaline(Compound A41 Step 1

In DMSO (5 mL) was dissolved 2-methyl-1H-imidazole (575 mg, 7.00 mmol).To the solution 60% sodium hydride (in oil) (323 mg, 8.08 mmol) wasadded at 0° C. and the mixture was stirred at room temperature for 30minutes. Ethyl 6-chloronicotinate (1.00 g, 5.39 mmol) was added and themixture was stirred at room temperature for 30 minutes. Water was addedto the reaction mixture. Extraction with ethyl acetate, washing withsaturated brine and drying over anhydrous sodium sulfate were performed.After filtration, the solvent in the filtrate was evaporated underreduced pressure. The residue was purified by silica gel columnchromatography (chloroform/methanol=97/3) to give ethyl6-(2-methyl-1H-imidazol-1-yl)nicotinate (455 mg, 37% yield).

Step 2

Lithium aluminum hydride (164 mg, 4.33 mmol) was suspended in THF (5mL). A solution of ethyl 6-(2-methyl-1H-imidazol-1-yl)nicotinate (455mg, 1.96 mmol) obtained in Step 1 in THF (5 mL) was added at 0° C. andthe mixture was stirred at 0° C. for 30 minutes. To the reaction mixturewere sequentially added water (0.146 mL), a 15% aqueous sodium hydroxidesolution (0.146 mL), and water (0.492 mL), and the mixture was stirredat room temperature for 1 hour. The reaction mixture was filteredthrough Celite. The solvent in the filtrate was evaporated under reducedpressure. The residue was purified by silica gel column chromatography(chloroform/methanol=97/3) to give(6-(2-methyl-1H-imidazol-1-yl)pyridin-3-yl)methanol (341 mg, 92% yield).

Step 3

In dichloromethane (5 mL) was dissolved(6-(2-methyl-1H-imidazol-1-yl)pyridin-3-yl)methanol (340 mg, 1.80 mmol)obtained in Step 2. Dess-Martin periodinane (915 mg, 2.16 mmol) wasadded and the mixture was stirred at room temperature for 1 hour. To thereaction mixture were added a saturated aqueous sodium bicarbonatesolution and a saturated aqueous sodium thiosulfate solution and themixture was stirred at room temperature for 1 hour. Extraction withdichloromethane and drying over anhydrous sodium sulfate were performed.After filtration, the solvent in the filtrate was evaporated underreduced pressure. The residue was purified by silica gel columnchromatography (chloroform/methanol=19/1) to give6-(2-methyl-1H-imidazol-1-yl)nicotinaldehyde (292 mg, 87% yield).

Step 4

According to Step 1 of Reference Example 10,2,2,2-trifluoro-1-(6-(2-methyl-1H-imidazol-1-yl)pyridin-3-yl)ethanol(272 mg, 68% yield) was obtained from6-(2-methyl-1H-imidazol-1-yl)nicotinaldehyde (292 mg, 1.56 mmol)obtained in Step 2.

Step 5

According to Step 3 of Reference Example 9, Compound A41 (104 mg, 89%yield) was obtained from2,2,2-trifluoro-1-(6-(2-methyl-1H-imidazol-1-yl)pyridin-3-yl)ethanol(72.0 mg, 0.280 mg) obtained in Step 4.

Reference Example 421-(4-(1-(3-chloroquinoxalin-2-yloxy)-2,2,2-trifluoroethyl)pyridin-2-yl)ethanone (Compound A42 Step 1

According to Step 1 of Reference Example 10,1-(2-bromopyridin-4-yl)-2,2,2-trifluoroethanol (7.96 g, 58% yield) wasobtained from 2-bromoisonicotinaldehyde (9.90 g, 53.2 mmol).

Step 2

In dichloromethane (50 mL) was dissolved1-(2-bromopyridin-4-yl)-2,2,2-trifluoroethanol (5.00 g, 19.5 mmol)obtained in Step 1. Triethylamine (10.2 mL, 73.2 mmol) andtert-butyldimethylsilyl trifluoromethanesulfonate (7.41 mL, 32.3 mmol)were added under ice-cooling and the mixture was stirred at roomtemperature for 9.5 hours. Water was added to the reaction mixture.Extraction with ethyl acetate and drying over anhydrous magnesiumsulfate were performed. After filtration, the solvent in the filtratewas evaporated under reduced pressure. The residue was purified bysilica gel column chromatography (hexane/ethyl acetate=4/1) to give2-bromo-4-(1-(tert-butyldimethylsilyloxy)-2,2,2-trifluoroethyl)pyridine(6.43 g, 89% yield).

Step 3

To toluene (9 mL) were added dropwise at −78° C. n-butyllithium (2.66mol/L solution in n-hexane, 1.12 mL, 2.97 mmol) and a solution of2-bromo-4-(1-(tert-butyldimethylsilyloxy)-2,2,2-trifluoroethyl)pyridine(1.00 g, 2.70 mmol) obtained in Step 2 in toluene (3.0 mL), and themixture was stirred at the same temperature for 30 minutes. THF (3.0 mL)was added to the resulting solution and the mixture was stirred at −78°C. for 30 minutes. N-methoxy-N-methylacetamide (1.38 mL, 13.5 mmol) wasadded and the mixture was stirred for 2 hours allowing the temperatureto rise slowly to room temperature. A saturated aqueous ammoniumchloride solution and water were added to the reaction mixture.Extraction with ethyl acetate and drying over anhydrous magnesiumsulfate were performed. After filtration, the solvent in the filtratewas evaporated under reduced pressure. The residue was purified bysilica gel column chromatography (hexane/ethyl acetate=4/1) to give1-(4-(1-(tert-butyldimethylsilyloxy)-2,2,2-trifluoroethyl)pyridin-2-yl)ethanone (645 mg, 72% yield).

Step 4

In THE (6 mL) was dissolved1-(4-(1-(tert-butyldimethylsilyloxy)-2,2,2-trifluoroethyl)pyridin-2-yl)ethanone (645 mg, 1.93 mmol) obtained in Step 3.Tetrabutylammonium fluoride (1.0 mol/L solution in THF, 0.556 mL, 0.556mmol) was added and the mixture was stirred at room temperature for 1hour. A saturated aqueous ammonium chloride solution was added to thereaction mixture. Extraction with ethyl acetate and drying overanhydrous magnesium sulfate were performed. After filtration, thesolvent in the filtrate was evaporated under reduced pressure. Theresidue was purified by silica gel column chromatography (hexane/ethylacetate=1/1) to give 1-(4-(2,2,2-trifluoro-1-hydroxyethyl)pyridin-2-yl)ethanone (406 mg, 96% yield).

Step 5

According to Step 3 of Reference Example 9, Compound A42 (227 mg, 37%yield) was obtained from1-(4-(2,2,2-trifluoro-1-hydroxyethyl)pyridin-2-yl) ethanone (350 mg,1.60 mmol) obtained in Step 4.

Reference Example 432,2,2-trifluoro-1-(6-(2-methyl-2H-1,2,3-triazol-4-yl)pyridin-3-yl)ethanol (Compound A43 Step 1

In ethanol (60 mL) was dissolved 6-bromonicotinaldehyde (2.00 g, 10.8mmol). Triethyl orthoformate (5.37 mL, 32.3 mmol) and p-toluenesulfonicacid monohydrate (102 mg, 0.538 mmol) were added and the mixture wasrefluxed for 2 hours. The solvent in the reaction mixture was evaporatedunder reduced pressure, and a saturated aqueous sodium bicarbonatesolution and water were added. Extraction with ethyl acetate, washingwith saturated brine and drying over anhydrous sodium sulfate wereperformed. After filtration, the solvent in the filtrate was evaporatedunder reduced pressure. The residue was purified by silica gel columnchromatography (hexane/ethyl acetate=9/1) to give2-bromo-5-(diethoxymethyl)pyridine (2.59 g, 92% yield).

Step 2

In THF (10 mL) was dissolved 2-bromo-5-(diethoxymethyl)pyridine (1.00 g,3.84 mmol) obtained in Step 1. To the solution were added trimethylsilylacetylene (1.09 mL, 7.69 mmol), copper iodide (I) (37.0 mg, 0.192 mmol),(bistriphenylphosphine) palladium (II) chloride (135 mg, 0.192 mmol),and triethylamine (1.07 mL, 7.69 mmol), and the mixture was stirred at70° C. for 6 hours. The solvent in the reaction mixture was evaporatedunder reduced pressure, and water and ethyl acetate were added. Themixture was filtered through Celite and the filtrate was extracted withethyl acetate. Washing with saturated brine and drying over anhydroussodium sulfate were performed. After filtration, the solvent in thefiltrate was evaporated under reduced pressure. The residue was purifiedby silica gel column chromatography (hexane/ethyl acetate=9/1) to give5-(diethoxymethyl)-2-((trimethylsilyl) ethynyl)pyridine (1.07 g). Inmethanol (10 mL) was dissolved 5-(diethoxymethyl)-2-((trimethylsilyl)ethynyl)pyridine obtained. Potassium carbonate (1.06 g, 7.69 mmol) wasadded, and the mixture was stirred at room temperature for 1 hour. Thesolvent in the reaction mixture was evaporated under reduced pressure,and water was added. Extraction with ethyl acetate, washing withsaturated brine and drying over anhydrous sodium sulfate were performed.After filtration, the solvent in the filtrate was evaporated underreduced pressure. The residue was purified by silica gel columnchromatography (hexane/ethyl acetate=4/1) to give5-(diethoxymethyl)-2-ethynylpyridine (703 mg, 89% yield).

Step 3

In tert-butanol (10 mL) was dissolved5-(diethoxymethyl)-2-ethynylpyridine (1.41 g, 6.87 mmol) obtained inStep 2. To the solution were added azidomethyl pivalate (1.08 g, 6.87mmol), water (10 mL), copper (II) sulfate pentahydrate (86.0 mg, 0.343mmol) and sodium ascorbate (408 mg, 0.343 mmol), and the mixture wasstirred at room temperature for 3 hours. Water was added to the reactionmixture. Extraction with ethyl acetate, washing with saturated brine anddrying over anhydrous sodium sulfate were performed. After filtration,the solvent in the filtrate was evaporated under reduced pressure. Theresidue was purified by silica gel column chromatography (hexane/ethylacetate=4/1) to give(4-(5-(diethoxymethyl)pyridin-2-yl)-1H-1,2,3-triazol-1-yl)methylpivalate (2.27 g, 91% yield).

Step 4 In methanol (12 mL) was dissolved(4-(5-(diethoxymethyl)pyridin-2-yl)-1H-1,2,3-triazol-1-yl)methylpivalate (1.96 g, 5.41 mmol) obtained in Step 3. To the solution wasadded a 1 mol/L aqueous sodium hydroxide solution (11.9 mL, 11.9 mmol)and the mixture was stirred at room temperature for 5 minutes. To thereaction mixture were added 1 mol/L hydrochloric acid (11.9 mL) andwater. Extraction with ethyl acetate, washing with saturated brine anddrying over anhydrous sodium sulfate were performed. After filtration,the solvent in the filtrate was evaporated under reduced pressure togive 5-(diethoxymethyl)-2-(1H-1,2,3-triazol-4-yl)pyridine (1.34 g, 100%yield).

Step 5

In acetonitrile (25 mL) was dissolved 5-(diethoxymethyl)-2-(1H-1, 2,3-triazol-4-yl)pyridine (1.34 g, 5.40 mmol) obtained in Step 4. To thesolution were added potassium carbonate (2.24 g, 5.40 mmol) andiodomethane (0.405 mL, 6.48 mmol) and the mixture was stirred at roomtemperature for 5 hours. The reaction mixture was concentrated underreduced pressure and water was added. Extraction with ethyl acetate,washing with saturated brine and drying over anhydrous sodium sulfatewere performed. After filtration, the solvent in the filtrate wasevaporated under reduced pressure. The residue was purified by silicagel column chromatography (hexane/ethyl acetate=4/1) to give5-(diethoxymethyl)-2-(2-methyl-2H-1,2,3-triazol-4-yl)pyridine (698 mg,49% yield).

Step 6

In THF (6.5 mL) was dissolved5-(diethoxymethyl)-2-(2-methyl-2H-1,2,3-triazol-4-yl)pyridine (672 mg,2.56 mmol) obtained in Step 5. To the solution was added 1 mol/Lhydrochloric acid (6.40 mL, 6.40 mmol) and the mixture was stirred atroom temperature for 2 hours. A saturated aqueous sodium bicarbonatesolution was added to the reaction mixture. Extraction with ethylacetate, washing with saturated brine and drying over anhydrous sodiumsulfate were performed. After filtration, the solvent in the filtratewas evaporated under reduced pressure. The residue was purified bysilica gel column chromatography (hexane/ethyl acetate=7/3) to give6-(2-methyl-2H-1,2,3-triazol-4-yl) nicotinaldehyde (473 mg, 98% yield).

Step 7

According to Step 1 of Reference Example 10, Compound A43 (672 mg, 85%yield) was obtained from6-(2-methyl-2H-1,2,3-triazol-4-yl)nicotinaldehyde (453 mg, 2.41 mmol)obtained in Step 6.

Reference Example 442,2,2-trifluoro-1-(6-(oxazol-5-yl)pyridin-3-yl)ethanol (Compound A44Step 1

To toluene (3 mL) were added dropwise at −78° C. n-butyllithium (2.6mol/L solution in n-hexane, 0.94 mL, 2.43 mmol) and a solution of2-bromo-5-(diethoxymethyl)pyridine (575 mg, 2.21 mmol) obtained in Step1 of Reference Example 42 in toluene (2 mL), and the mixture was stirredat −78° C. for 30 minutes. THF (2 mL) was added to the resultingsuspension and the mixture was stirred at −78° C. for 30 minutes. DMF(0.51 mL, 6.63 mmol) was added and the mixture was stirred for 30minutes allowing the temperature to rise slowly to room temperature. Asaturated aqueous ammonium chloride solution and water were added to thereaction mixture. Extraction with ethyl acetate, washing with saturatedbrine and drying over anhydrous sodium sulfate were performed. Afterfiltration, the solvent in the filtrate was evaporated under reducedpressure. The residue was purified by silica gel column chromatography(hexane/ethyl acetate=9/1) to give 5-(diethoxymethyl)picolinaldehyde(149 mg, 32% yield).

Step 2

In methanol (5 mL) was dissolved 5-(diethoxymethyl)picolinaldehyde (148mg, 0.707 mmol) obtained in Step 1. To the solution were addedtoluene-4-sulfonylmethylisocyanide (345 mg, 1.77 mmol) and potassiumcarbonate (244 mg, 1.77 mmol) and the mixture was stirred at roomtemperature for 8 hours. Water was added to the reaction mixture.Extraction with ethyl acetate, washing with saturated brine and dryingover anhydrous sodium sulfate were performed. After filtration, thesolvent in the filtrate was evaporated under reduced pressure. Theresidue was purified by silica gel column chromatography (hexane/ethylacetate=7/3) to give 5-(5-(diethoxymethyl)pyridin-2-yl)oxazole (161 mg,92% yield).

Step 3

According to Step 6 of Reference Example 43,6-(oxazol-5-yl)nicotinaldehyde (98.1 mg, 88% yield) was obtained from5-(5-(diethoxymethyl)pyridin-2-yl)oxazole (160 mg, 0.647 mmol) obtainedin Step 2.

Step 4

According to Step 1 of Reference Example 10, Compound A44 (124 mg, 90%yield) was obtained from 6-(oxazol-5-yl)nicotinaldehyde (98.2 mg, 0.564mmol) obtained in Step 3.

Reference Example 451-(1,2-dimethyl-1H-imidazol-5-yl)-2,2,2-trifluoroethanol (Compound A45Step 1

In DMF (10 mL) was dissolved 2-methyl-1H-imidazole-5-carbaldehyde (1.00g, 9.08 mmol). Potassium carbonate (2.51 g, 18.2 mmol) and methylp-toluenesulfonate (2.06 mL, 13.6 mmol) were added under ice-cooling andthe mixture was stirred at room temperature for 6 hours. A 1 mol/Laqueous sodium hydroxide solution and water were added to the reactionmixture. Extraction with ethyl acetate, washing with a 1 mol/L aqueoussodium hydroxide solution and drying over anhydrous magnesium sulfatewere performed. After filtration, the solvent in the filtrate wasevaporated under reduced pressure. The residue was purified by silicagel column chromatography (chloroform/methanol=19/1) to give1,2-dimethyl-1H-imidazole-5-carbaldehyde (180 mg, 16% yield).

Step 2

According to Step 1 of Reference Example 10, Compound A45 (232 mg, 85%)was obtained from 1,2-dimethyl-1H-imidazole-5-carbaldehyde (180 mg, 1.45mmol) obtained in Step 1.

Reference Example 461-(5-(2,2,2-trifluoro-1-hydroxyethyl)thiazol-2-yl)ethanone (Compound A46Step 1

According to Step 1 of Reference Example 10,1-(2-bromothiazol-5-yl)-2,2,2-trifluoroethanol (413 mg, 25%) wasobtained from 2-bromothiazole-5-carbaldehyde (1.20 g, 6.25 mmol).

Step 2

According to Step 2 of Reference Example 42,2-bromo-5-(1-(tert-butyldimethylsilyloxy)-2,2,2-trifluoroethyl)thiazole(524 mg, 88%) was obtained from1-(2-bromothiazol-5-yl)-2,2,2-trifluoroethanol (413 mg, 1.58 mmol)obtained in Step 1.

Step 3

In THF (5 mL) was dissolved2-bromo-5-(1-(tert-butyldimethylsilyloxy)-2,2,2-trifluoroethyl)thiazole(515 mg, 1.37 mmol) obtained in Step 2. n-Butyllithium (1.65 mol/Lsolution in n-hexane, 1.24 mL, 2.05 mmol) was added dropwise at −78° C.and the mixture was stirred at −78° C. for 30 minutes. A solution ofN-methoxy-N-methylacetamide (1.38 mL, 13.7 mmol) in THF (1 mL) was addedto the reaction mixture and the mixture was stirred at −78° C. for 2hours. A saturated aqueous ammonium chloride solution and water wereadded to the reaction mixture. Extraction with ethyl acetate and dryingover anhydrous magnesium sulfate were performed. After filtration, thesolvent in the filtrate was evaporated under reduced pressure. Theresidue was purified by silica gel column chromatography (hexane/ethylacetate=4/1) to give1-(5-(1-(tert-butyldimethylsilyloxy)-2,2,2-trifluoroethyl)thiazol-2-yl)ethanone (437 mg, 94%).

Step 4

In THF (3 mL) was dissolved1-(5-(1-(tert-butyldimethylsilyloxy)-2,2,2-trifluoroethyl)thiazol-2-yl)ethanone (356 mg, 1.05 mmol) obtained in Step 3. To thesolution were added acetic acid (0.072 mL, 1.26 mmol) andtetrabutylammonium fluoride (1.0 mol/L solution in THF, 1.26 mL, 1.26mmol) and the mixture was stirred at room temperature for 1 hour. Asaturated aqueous sodium carbonate solution was added to the reactionmixture. Extraction with ethyl acetate, washing with a saturated aqueousammonium chloride solution and drying over anhydrous magnesium sulfatewere performed. After filtration, the solvent in the filtrate wasevaporated under reduced pressure. The residue was purified by silicagel column chromatography (hexane/ethyl acetate=1/1) to give CompoundA46 (214 mg, 91%).

Reference Example 473-chloro-6-iodo-2-(2,2,2-trifluoro-1-(pyridin-3-yl)ethoxy) quinoxaline(Compound A47) Step 1

According to Step 1 of Reference Example 10,2,2,2-trifluoro-1-(pyridin-3-yl)ethanol (16.6 g, 99% yield) was obtainedfrom nicotinaldehyde (9.00 mL, 95.4 mmol).

Step 2

In THF (200 mL) was dissolved 2,3-dichloro-6-nitroquinoxaline (4.00 g,16.4 mmol) and the mixture was cooled to −78° C. To the solution wereadded 2,2,2-trifluoro-1-(pyridin-3-yl)ethanol (3.05 g, 17.2 mmol)obtained in Step 1 and sodium hydride (1.31 g, 32.8 mmol) and themixture was stirred at −78° C. allowing the temperature to rise slowlyto −30° C. over 1 hour. A saturated aqueous ammonium chloride solutionwas added to the reaction mixture. Extraction with ethyl acetate,washing with saturated brine and drying over anhydrous magnesium sulfatewere performed. After filtration, the solvent in the filtrate wasevaporated under reduced pressure. The residue was purified by silicagel column chromatography (hexane/ethyl acetate=1/0 to 3/2) to give3-chloro-6-nitro-2-(2,2,2-trifluoro-1-(pyridin-3-yl)ethoxy) quinoxaline(3.98 g, 63% yield).

ESIMS m/z: 385 (M+H)⁺.

Step 3

In a mixed solvent of ethanol (19.5 mL) and water (9.75 mL) wasdissolved3-chloro-6-nitro-2-(2,2,2-trifluoro-1-(pyridin-3-yl)ethoxy)quinoxaline(975 mg, 2.53 mmol) obtained in Step 2. To the solution were added iron(0) (425 mg, 7.60 mmol) and ammonium chloride (68.0 mg, 1.27 mmol) andthe mixture was stirred at 80° C. for 1 hour. The reaction mixture wasfiltered through Celite and the filtrate was extracted with ethylacetate. Washing with saturated brine and drying over anhydrousmagnesium sulfate were performed. After filtration, the solvent in thefiltrate was evaporated under reduced pressure. The residue was purifiedby silica gel column chromatography (hexane/ethyl acetate=1/0 to 0/1) togive 3-chloro-2-(2,2,2-trifluoro-1-(pyridin-3-yl)ethoxy)quinoxaline-6-amine (555 mg, 62% yield).

ESIMS m/z: 355 (M+H)⁺.

Step 4

In 2.0 mol/L hydrochloric acid (50.0 mL) was dissolved3-chloro-2-(2,2,2-trifluoro-1-(pyridin-3-yl)ethoxy) quinoxaline-6-amine(2.00 g, 5.64 mmol) obtained in Step 3 and the mixture was cooled to 0°C. Sodium nitrite (506 mg, 7.33 mmol) was added and the mixture wasstirred at 0° C. for 10 minutes. Urea (508 mg, 8.46 mmol) was added tothe reaction mixture and the mixture was stirred at 0° C. for 10minutes. Potassium iodide (2.34 g, 14.1 mmol) dissolved in water (10.0mL) was slowly added and the mixture was stirred at room temperature for30 minutes. A saturated aqueous sodium bicarbonate solution and asaturated aqueous sodium thiosulfate solution were added to the reactionmixture. Extraction with ethyl acetate, washing with saturated brine anddrying over anhydrous magnesium sulfate were performed. Afterfiltration, the solvent in the filtrate was evaporated under reducedpressure. The residue was purified by silica gel column chromatography(hexane/ethyl acetate=1/0 to 3/2) to give Compound A47 (868 mg, 33%yield).

ESIMS m/z: 466 (M+H)⁺.

Example 1 N-(3-(2-hydroxy-2-methyl-1-(pyridin-3-yl)propoxy)quinoxalin-2-yl)propane-1-sulfonamide (Compound 1

In THF (5 mL) were dissolved Compound A1 (235 mg, 0.821 mmol) obtainedin Reference Example 1 and Compound A14 (206 mg, 1.23 mmol) obtained inReference Example 14. To the mixture was added 60% sodium hydride (inoil, 82.1 mg, 2.05 mmol) and the mixture was stirred at 50° C. for 9hours. A saturated aqueous ammonium chloride solution and water wereadded to the reaction mixture. Extraction with ethyl acetate, washingwith saturated brine and drying over anhydrous sodium sulfate wereperformed. After filtration, the solvent in the filtrate was evaporatedunder reduced pressure. The residue was purified by silica gel columnchromatography (ethyl acetate: 100%) to give Compound 1 (279 mg, 82%yield).

ESIMS m/z: 417 (M+H)⁺.

Example 23-(2-hydroxy-2-methyl-1-(3-(propylsulfonamido)quinoxalin-2-yloxy)propyl)pyridine1-oxide (Compound 2

Compound 1 (89.6 mg, 0.215 mmol) obtained in Example 1 was dissolved indichloromethane (5.0 mL). To the solution was added 65%meta-chloroperbenzoic acid (85.7 mg, 0.323 mmol) and the mixture wasstirred at room temperature for 2 hours. The solvent was evaporatedunder reduced pressure. The residue was purified by preparativethin-layer chromatography (chloroform/methanol=9/1) to give Compound 2(47.7 mg, 51% yield).

ESIMS m/z: 433 (M+H)⁺.

Example 3 N-(3-(2,2-dimethyl-1-(pyridin-3-yl)propoxy)quinoxalin-2-yl)propane-1-sulfonamide (Compound 3

According to Example 1, Compound 3 (189 mg, 65% yield) was obtained fromCompound A1 (200 mg, 0.700 mmol) obtained in Reference Example 1 andCompound A15 (173 mg, 1.05 mmol) obtained in Reference Example 15.

ESIMS m/z: 415 (M+H)⁺.

Example 4 3-(2,2-dimethyl-1-(3-(propylsulfonamido)quinoxalin-2-yloxy)propyl)pyridine 1-oxide (Compound 4

According to Example 2, Compound 4 (135 mg, 97% yield) was obtained fromCompound 3 (134 mg, 0.323 mmol) obtained in Example 3.

ESIMS m/z: 431 (M+H)⁺.

Example 5 N-(3-(cyclopropyl(pyridin-3-yl)methoxy)quinoxalin-2-yl)propane-1-sulfonamide (Compound 5

According to Example 1, Compound 5 (209 mg, 75% yield) was obtained fromCompound A1 (200 mg, 0.700 mmol) obtained in Reference Example 1 andCompound A16 (157 mg, 1.05 mmol) obtained in Reference Example 16.

ESIMS m/z: 399 (M+H)⁺.

Example 63-(cyclopropyl(3-(propylsulfonamido)quinoxalin-2-yloxy)methyl)pyridine1-oxide (Compound 6

According to Example 2, Compound 6 (135 mg, 93% yield) was obtained fromCompound 5 (140 mg, 0.351 mmol) obtained in Example 5.

ESIMS m/z: 415 (M+H)⁺.

Example 7N-(3-(2-fluoro-2-methyl-1-(pyridin-3-yl)propoxy)quinoxalin-2-yl)propane-1-sulfonamide(Compound 7

According to Example 1, Compound 7 (274 mg, 93% yield) was obtained fromCompound A1 (200 mg, 0.700 mmol) obtained in Reference Example 1 andCompound A17 (178 mg, 1.05 mmol) obtained in Reference Example 17.

ESIMS m/z: 419 (M+H)⁺.

Example 83-(2-fluoro-2-methyl-1-(3-(propylsulfonamido)quinoxalin-2-yloxy)propyl)pyridine1-oxide (Compound 8

According to Example 2, Compound 8 (197 mg, 98% yield) was obtained fromCompound 7 (194 mg, 0.464 mmol) obtained in Example 7.

ESIMS m/z: 435 (M+H)⁺.

¹H-NMR (300 MHz, CDCl₃, δ): 1.12 (t, J=7.7 Hz, 3H), 1.39-1.64 (m, 6H),1.93-2.05 (m, 2H), 3.77 (s, 2H), 6.26 (d, J=20.2 Hz, 1H), 7.28-7.89 (m,6H), 8.57 (dd, J=1.8, 4.8 Hz, 1H), 8.77 (d, J=1.8 Hz, 1H).

Example 9N-(3-(pyridin-3-ylmethoxy)quinoxalin-2-yl)propane-1-sulfonamide(Compound 9

According to Example 1, Compound 9 (102 mg, 81% yield) was obtained fromCompound A1 (100 mg, 0.350 mmol) obtained in Reference Example 1 and3-pyridinemethanol (57.3 mg, 0.525 mmol).

ESIMS m/z: 359 (M+H)⁺.

Example 10 3-((3-(propylsulfonamido)quinoxalin-2-yloxy)methyl)pyridine1-oxide (Compound 10

According to Example 2, Compound 10 (51.0 mg, 92% yield) was obtainedfrom Compound 9 (53.1 mg, 0.148 mmol) obtained in Example 9.

ESIMS m/z: 375 (M+H)⁺.

Example 11N-(3-(1-(pyridin-3-yl)pentyloxy)quinoxalin-2-yl)propane-1-sulfonamide(Compound 11

According to Example 1, Compound 11 (202 mg, 93% yield) was obtainedfrom Compound A1 (150 mg, 0.525 mmol) obtained in Reference Example 1and Compound A18 (130 mg, 0.787 mmol) obtained in Reference Example 18.

ESIMS m/z: 415 (M+H)⁺.

Example 12 3-(1-(3-(propylsulfonamido)quinoxalin-2-yloxy)pentyl)pyridine1-oxide (Compound 12

According to Example 2, Compound 12 (81.5 mg, 77% yield) was obtainedfrom Compound 11 (102 mg, 0.246 mmol) obtained in Example 11.

ESIMS m/z: 431 (M+H)⁺.

Example 13 N-(3-((1-methylcyclopropyl) (pyridin-3-yl)methoxy)quinoxalin-2-yl)propane-1-sulfonamide (Compound 13

Compound A9 (147 mg, 0.451 mmol) obtained in Reference Example 9 andpropane-1-sulfonamide (61.1 mg, 0.496 mol) were dissolved in DMSO (3.0mL). Potassium carbonate (68.6 mg, 0.496 mmol) was added, and themixture was stirred at 150° C. for 1 hour. A saturated aqueous ammoniumchloride solution and water were added to the reaction mixture.Extraction with ethyl acetate, washing with saturated brine and dryingover anhydrous sodium sulfate were performed. After filtration, thesolvent in the filtrate was evaporated under reduced pressure. Theresidue was purified by silica gel column chromatography (hexane/ethylacetate=7/3) to give Compound 13 (136 mg, 73% yield). ESIMS m/z: 413(M+H)⁺.

Example 143-((1-methylcyclopropyl)(3-(propylsulfonamido)quinoxalin-2-yloxy)methyl)pyridine1-oxide (Compound 14

According to Example 2, Compound 14 (84.5 mg, 81% yield) was obtainedfrom Compound 13 (100 mg, 0.242 mmol) obtained in Example 13.

ESIMS m/z: 429 (M+H)⁺.

Example 15N-(3-(1-(pyridin-3-yl)propoxy)quinoxalin-2-yl)propane-1-sulfonamide(Compound 15

According to Example 1, Compound 15 (163 mg, 80% yield) was obtainedfrom Compound A1 (150 mg, 0.525 mmol) obtained in Reference Example 1and Compound A19 (103 mg, 0.752 mmol) obtained in Reference Example 19.

ESIMS m/z: 387 (M+H)⁺.

Example 16 3-(1-(3-(propylsulfonamido)quinoxalin-2-yloxy)propyl)pyridine1-oxide (Compound 16

According to Example 2, Compound 16 (95.6 mg, 92% yield) was obtainedfrom Compound 15 (100 mg, 0.259 mmol) obtained in Example 15.

ESIMS m/z: 402 (M+H)⁺.

Example 17 N-(3-(2,2-difluoro-1-(pyridin-3-yl)ethoxy)quinoxalin-2-yl)propane-1-sulfonamide (Compound 17

According to Example 1, Compound 17 (159 mg, 74% yield) was obtainedfrom Compound A1 (150 mg, 0.525 mmol) obtained in Reference Example 1and Compound A20 (121 mg, 0.760 mmol) obtained in Reference Example 20.

ESIMS m/z: 409 (M+H)⁺.

Example 183-(2,2-difluoro-1-(3-(propylsulfonamido)quinoxalin-2-yloxy)ethyl)pyridine1-oxide (Compound 18

According to Example 2, Compound 18 (97.5 mg, 96% yield) was obtainedfrom Compound 17 (100 mg, 0.245 mmol) obtained in Example 17.

ESIMS m/z: 424 (M+H)⁺.

Example 19N-(3-(1-(pyridin-3-yl)ethoxy)quinoxalin-2-yl)propane-1-sulfonamide(Compound 19

According to Example 1, Compound 19 (128 mg, 65% yield) was obtainedfrom Compound A1 (150 mg, 0.525 mmol) obtained in Reference Example 1and Compound A21 (96.7 mg, 0.787 mmol) obtained in Reference Example 21.

ESIMS m/z: 373 (M+H)⁺.

Example 20 3-(1-(3-(propylsulfonamido)quinoxalin-2-yloxy)ethyl)pyridine1-oxide (Compound 20

According to Example 2, Compound 20 (87.3 mg, 100% yield) was obtainedfrom Compound 19 (73.3 mg, 0.197 mmol) obtained in Example 19.

ESIMS m/z: 389 (M+H)⁺.

Example 21N-(3-(1-(pyridin-3-yl)butoxy)quinoxalin-2-yl)propane-1-sulfonamide(Compound 21

According to Example 1, Compound 21 (179 mg, 85% yield) was obtainedfrom Compound A1 (150 mg, 0.525 mmol) obtained in Reference Example 1and Compound A22 (119 mg, 0.787 mmol) obtained in Reference Example 22.

ESIMS m/z: 401 (M+H)⁺.

Example 22 3-(1-(3-(propylsulfonamido)quinoxalin-2-yloxy)butyl)pyridine1-oxide (Compound 22

According to Example 2, Compound 22 (112 mg, 81% yield) was obtainedfrom Compound 21 (120 mg, 0.300 mmol) obtained in Example 21.

ESIMS m/z: 417 (M+H)⁺.

Example 23N-(3-(phenyl(pyridin-3-yl)methoxy)quinoxalin-2-yl)propane-1-sulfonamide(Compound 23

According to Example 1, Compound 23 (155 mg, 100% yield) was obtainedfrom Compound A1 (150 mg, 0.525 mmol) obtained in Reference Example 1and Compound A23 (144 mg, 0.787 mmol) obtained in Reference Example 23.

ESIMS m/z: 435 (M+H)⁺.

Example 243-(phenyl(3-(propylsulfonamido)quinoxalin-2-yloxy)methyl)pyridine1-oxide (Compound 24

According to Example 2, Compound 24 (89.8 mg, 89% yield) was obtainedfrom Compound 23 (97.7 mg, 0.225 mmol) obtained in Example 23.

ESIMS m/z: 451 (M+H)⁺.

Example 25 N-(3-(2,2,2-trifluoro-1-(4-(methylsulfonyl)phenyl)ethoxy)quinoxalin-2-yl)propane-1-sulfonamide (Compound 25

According to Example 13, Compound 25 (59.2 mg, 49% yield) was obtainedfrom Compound A10 (100 mg, 0.240 mmol) obtained in Reference Example 10.

ESIMS m/z: 504 (M+H)⁺.

Example 26 N-(3-(1-(6-cyanopyridin-3-yl)-2,2,2-trifluoroethoxy)quinoxalin-2-yl)propane-1-sulfonamide (Compound 26

According to Example 13, Compound 26 (23.5 mg, 14% yield) was obtainedfrom Compound A11 (133 mg, 0.362 mmol) obtained in Reference Example 11.

ESIMS m/z: 452 (M+H)⁺.

Example 27 N-(3-(2,2,2-trifluoro-1-(imidazo[1,2-a]pyridin-6-yl)ethoxy)quinoxalin-2-yl)propane-1-sulfonamide (Compound 27

According to Example 1, Compound 27 (82.4 mg, 77% yield) was obtainedfrom Compound A1 (66.1 mg, 0.231 mmol) obtained in Reference Example 1and Compound A24 (50.0 mg, 0.231 mmol) obtained in Reference Example 24.

ESIMS m/z: 467 (M+H)⁺.

Example 28 N-(3-(2,2,2-trifluoro-1-(imidazo[1,2-a]pyridin-6-yl)ethoxy)quinoxalin-2-yl)butane-1-sulfonamide (Compound 28

According to Example 1, Compound 28 (69.6 mg, 63% yield) was obtainedfrom Compound A2 (69.2 mg, 0.231 mmol) obtained in Reference Example 2and Compound A24 (50.0 mg, 0.231 mmol) obtained in Reference Example 24.

ESIMS m/z: 480 (M+H)⁺.

Example 292-methyl-N-(3-(2,2,2-trifluoro-1-(imidazo[1,2-a]pyridin-6-yl)ethoxy)quinoxalin-2-yl)propane-1-sulfonamide(Compound 29

According to Example 1, Compound 29 (60.4 mg, 55% yield) was obtainedfrom Compound A3 (69.2 mg, 0.231 mmol) obtained in Reference Example 3and Compound A24 (50.0 mg, 0.231 mmol) obtained in Reference Example 24.

ESIMS m/z: 480 (M+H)⁺.

Example 301-cyclopropyl-N-(3-(2,2,2-trifluoro-1-(imidazo[1,2-a]pyridin-6-yl)ethoxy)quinoxalin-2-yl)methanesulfonamide(Compound 30

According to Example 1, Compound 30 (102 mg, 92% yield) was obtainedfrom Compound A4 (68.8 mg, 0.231 mmol) obtained in Reference Example 4and Compound A24 (50.0 mg, 0.231 mmol) obtained in Reference Example 24.

ESIMS m/z: 478 (M+H)⁺.

Example 31 N-(3-(2,2,2-trifluoro-1-(6-(hydroxymethyl)pyridin-3-yl)ethoxy)quinoxalin-2-yl)propane-1-sulfonamide (Compound 31 Step 1N-(3-(2,2,2-trifluoro-1-(6-methylpyridin-3-yl)ethoxy)quinoxalin-2-yl)propane-1-sulfonamide (Compound B1

According to Example 1, Compound B1 (690 mg, 64% yield) was obtainedfrom Compound A1 (703 mg, 2.46 mmol) obtained in Reference Example 1 andCompound A25 (470 mg, 2.46 mmol) obtained in Reference Example 25.

Step 2 2-methyl-5-(2,2,2-trifluoro-1-(3-(propylsulfonamido)quinoxalin-2-yloxy)ethyl)pyridine 1-oxide (Compound B2

According to Example 2, Compound B2 (707 mg, 99% yield) was obtainedfrom Compound B1 (690 mg, 1.57 mmol) obtained in Step 1.

Step 3 N-(3-(2,2,2-trifluoro-1-(6-(hydroxymethyl)pyridin-3-yl)ethoxy)quinoxalin-2-yl)propane-1-sulfonamide (Compound 31

Compound B2 (103 mg, 0.226 mmol) obtained in Step 2 was suspended inacetic anhydride (1.0 mL) and the suspension was stirred at 100° C. for1.5 hours. Water was added to the reaction mixture. Extraction withethyl acetate, washing with saturated brine and drying over anhydroussodium sulfate were performed. The solvent was evaporated under reducedpressure and the resulting residue was dissolved in methanol (2.0 mL).Potassium carbonate (93.7 mg, 0.678 mmol) was added and the mixture wasstirred at room temperature for 30 minutes. The solvent was evaporatedunder reduced pressure, and a saturated aqueous ammonium chloridesolution and water were added. Extraction with ethyl acetate, washingwith saturated brine and drying over anhydrous sodium sulfate wereperformed. The solvent was evaporated under reduced pressure. Theresidue was purified by silica gel column chromatography (hexane/ethylacetate=1/1) and further purified by preparative thin-layerchromatography (hexane/ethyl acetate=1/1) to give Compound 31 (30.8 mg,30% yield).

ESIMS m/z: 457 (M+H)⁺.

¹H-NMR (300 MHz, CDCl₃, δ): 1.12 (t, J=7.3 Hz, 3H), 1.93-2.06 (m, 2H),3.49-3.78 (m, 3H), 4.79 (s, 2H), 6.79 (brs, 1H), 7.35-7.98 (m, 6H), 8.83(d, J=1.8 Hz, 1H).

Example 32 N-(3-(2,2,2-trifluoro-1-(6-(1-methyl-1H-pyrazol-4-yl)pyridin-3-yl)ethoxy)quinoxalin-2-yl)propane-1-sulfonamide (Compound 32

According to Example 1, Compound 32 (48.9 mg, 47% yield) was obtainedfrom Compound A1 (59.1 mg, 0.207 mmol) obtained in Reference Example 1and Compound A26 (53.2 mg, 0.207 mmol) obtained in Reference Example 26.

ESIMS m/z: 507 (M+H)⁺.

Example 33 N-(3-(2,2,2-trifluoro-1-(6-(1-methyl-1H-pyrazol-4-yl)pyridin-3-yl)ethoxy)quinoxalin-2-yl)butane-1-sulfonamide (Compound 33

According to Example 1, Compound 33 (52.8 mg, 49% yield) was obtainedfrom Compound A2 (62.1 mg, 0.207 mmol) obtained in Reference Example 2and Compound A26 (53.2 mg, 0.207 mmol) obtained in Reference Example 26.

ESIMS m/z: 521 (M+H)⁺.

¹H-NMR (300 MHz, CDCl₃, 8): 0.97 (t, J=7.3 Hz, 3H), 1.46-1.59 (m, 2H),1.89-1.99 (m, 2H), 3.81 (s, 2H), 3.95 (s, 3H), 6.78 (brs, 1H), 7.48-7.95(m, 8H), 8.79 (d, J=1.8 Hz, 1H).

Example 34 N-(3-(2,2,2-trifluoro-1-(6-(methylthio)pyridin-3-yl)ethoxy)quinoxalin-2-yl)propane-1-sulfonamide (Compound 34

According to Example 1, Compound 34 (278 mg, 77% yield) was obtainedfrom Compound A1 (218 mg, 0.763 mmol) obtained in Reference Example 1and Compound A27 (170 mg, 0.763 mmol) obtained in Reference Example 27.

ESIMS m/z: 473 (M+H)⁺.

Example 35 N-(3-(2,2,2-trifluoro-1-(6-(methylsulfonyl)pyridin-3-yl)ethoxy)quinoxalin-2-yl)propane-1-sulfonamide (Compound 35N-(3-(2,2,2-trifluoro-1-(6-(methylsulfinyl)pyridin-3-yl)ethoxy)quinoxalin-2-yl) propane-1-sulfonamide (Compound 36

Compound 34 (222 mg, 0.470 mmol) obtained in Example 34 was dissolved indichloromethane (5.0 mL), meta-chloroperbenzoic acid (67.8 mg, 1.17mmol) was added, and the mixture was stirred at room temperature for 2hours. A saturated aqueous sodium thiosulfate solution and water wereadded to the reaction mixture. Extraction with dichloromethane, washingwith saturated brine and drying over anhydrous sodium sulfate wereperformed. After filtration, the solvent in the filtrate was evaporatedunder reduced pressure. The residue was purified by silica gel columnchromatography (chloroform/methanol=1/1) to give Compound 35 (114 mg,48% yield) and Compound 36 (110 mg, 48% yield).

Compound 35: ESIMS m/z: 505 (M+H)⁺.

¹H-NMR (300 MHz, CDCl₃, S): 1.13 (t, J=6.9 Hz, 3H), 1.94-2.04 (m, 2H),3.25 (s, 3H), 4.12 (brs, 2H), 6.87 (brs, 1H), 7.56-7.30 (m, 6H), 9.00(s, 1H).

Compound 36: ESIMS m/z: 489 (M+H)⁺.

Example 36N-(3-(2,2,2-trifluoro-1-(6-(2-hydroxypropan-2-yl)pyridin-3-yl)ethoxy)quinoxalin-2-yl)propane-1-sulfonamide(Compound 37

According to Example 13, Compound 37 (63.0 mg, 61% yield) was obtainedfrom Compound A12 (83.1 mg, 0.209 mmol) obtained in Reference Example12.

ESIMS m/z: 490 (M+H)⁺.

Example 37 N-(3-(2,2,2-trifluoro-1-(6-(methylthio)pyridin-3-yl)ethoxy)quinoxalin-2-yl) butane-1-sulfonamide (Compound 38

According to Example 1, Compound 38 (179 mg, 57% yield) was obtainedfrom Compound A2 (195 mg, 0.650 mmol) obtained in Reference Example 2and Compound A27 (145 mg, 0.650 mmol) obtained in Reference Example 27.

ESIMS m/z: 487 (M+H)⁺.

Example 38N-(3-(2,2,2-trifluoro-1-(6-(2-hydroxypropan-2-yl)pyridin-3-yl)ethoxy)quinoxalin-2-yl)butane-1-sulfonamide(Compound 39

According to Example 13, Compound 39 (67.9 mg, 55% yield) was obtainedfrom Compound A12 (98.5 mg, 0.248 mmol) obtained in Reference Example12.

ESIMS m/z: 499 (M+H)⁺.

Example 39 N-(3-(2,2,2-trifluoro-1-(6-(methylsulfonyl)pyridin-3-yl)ethoxy)quinoxalin-2-yl) butane-1-sulfonamide (Compound 40N-(3-(2,2,2-trifluoro-1-(6-(methylsulfinyl)pyridin-3-yl)ethoxy)quinoxalin-2-yl) butane-1-sulfonamide (Compound 41

According to Example 35, Compound 40 (70.6 mg, 44% yield) and Compound41 (85.1 mg, 55% yield) were obtained from Compound 38 (149 mg, 0.306mmol) obtained in Example 37.

Compound 40: ESIMS m/z: 519 (M+H)⁺.

Compound 41: ESIMS m/z: 503 (M+H)⁺.

Example 40N-(3-(2,2,2-trifluoro-1-(pyridin-4-yl)ethoxy)quinoxalin-2-yl)propane-1-sulfonamide(Compound 42 Step 1N-(3-(2,2,2-trifluoro-1-(pyridin-4-yl)ethoxy)quinoxalin-2-yl)-N-((2-(trimethylsilyl)ethoxy)methyl)propane-1-sulfonamide(Compound B3

According to Example 1, Compound B3 (251 mg, 80% yield) was obtainedfrom Compound A5 (258 mg, 0.621 mmol) obtained in Reference Example 5and Compound A28 (100 mg, 0.565 mmol) obtained in Reference Example 28.

ESIMS m/z: 557 (M+H)⁺.

Step 2N-(3-(2,2,2-trifluoro-1-(pyridin-4-yl)ethoxy)quinoxalin-2-yl)propane-1-sulfonamide(Compound 42

Compound B3 (48.9 mg, 0.0880 mmol) obtained in Step 1 was dissolved intrifluoroacetic acid (1.0 mL) and the solution was stirred at roomtemperature for 20 minutes. The solvent was evaporated under reducedpressure. The residue was purified by silica gel column chromatography(hexane/ethyl acetate=1/1) to give Compound 42 (38.6 mg, 100% yield).

ESIMS m/z: 427 (M+H)⁺.

Example 414-(2,2,2-trifluoro-1-(3-(propylsulfonamido)quinoxalin-2-yloxy)ethyl)pyridine1-oxide (Compound 43

According to Example 2, Compound 43 (41.0 mg, 68% yield) was obtainedfrom Compound 42 (58.5 mg, 0.137 mmol) obtained in Example 40.

ESIMS m/z: 443 (M+H)⁺.

¹H-NMR (270 MHz, CDCl₃, S): 1.14 (t, J=7.7 Hz, 3H), 1.93-2.07 (m, 2H),3.72-3.86 (m, 2H), 6.55-6.76 (m, 1H), 7.42-7.96 (m, 6H), 8.24 (d, J=7.0Hz, 2H).

Example 42 N-(3-(1-(2-cyanopyridin-4-yl)-2,2,2-trifluoroethoxy)quinoxalin-2-yl)propane-1-sulfonamide (Compound 44 Step 14-(2,2,2-trifluoro-1-(3-(N-((2-(trimethylsilyl)ethoxy)methyl)propylsulfonamido)quinoxalin-2-yloxy)ethyl)pyridine 1-oxide (Compound B4

According to Example 2, Compound B4 (185 mg, 88% yield) was obtainedfrom Compound B3 (205 mg, 0.368 mmol) obtained in Step 1 of Example 40.

ESIMS m/z: 573 (M+H)⁺.

Step 2 N-(3-(1-(2-cyanopyridin-4-yl)-2,2,2-trifluoroethoxy)quinoxalin-2-yl)-N-((2-(trimethylsilyl)ethoxy)methyl)propane-1-sulfonamide (Compound B5

Compound B4 (210 mg, 0.367 mmol) obtained in Step 1 was dissolved indichloromethane (4 mL). To the solution were added trimethylsilylcyanide (0.25 mL, 1.8 mmol) and dimethylcarbamoyl chloride (0.17 mL, 1.8mmol), and the mixture was refluxed for 24 hours. A saturated aqueoussodium bicarbonate solution and water were added to the reactionmixture. Extraction with ethyl acetate and drying over anhydrous sodiumsulfate were performed. After filtration, the solvent in the filtratewas evaporated under reduced pressure. The residue was purified bysilica gel column chromatography (hexane/ethyl acetate=1/1) to giveCompound B5 (218 mg, 100% yield).

Step 3 N-(3-(1-(2-cyanopyridin-4-yl)-2,2,2-trifluoroethoxy)quinoxalin-2-yl)propane-1-sulfonamide (Compound 44

According to Step 2 of Example 40, Compound 44 (27.7 mg, 87% yield) wasobtained from Compound B5 (41.0 mg, 0.0700 mmol) obtained in Step 2.

ESIMS m/z: 452 (M+H)⁺.

¹H-NMR (270 MHz, CDCl₃, δ): 1.15 (t, J=7.7 Hz, 3H), 1.95-2.08 (m, 2H),3.81 (t, J=7.7 Hz, 2H), 6.64-6.79 (m, 1H), 7.32-7.96 (m, 6H), 8.83 (d,J=5.1 Hz, 1H).

Example 43 N-(3-(1-(2-aminopyridin-4-yl)-2,2,2-trifluoroethoxy)quinoxalin-2-yl)propane-1-sulfonamide (Compound 45

Compound B4 (200 mg, 0.349 mmol) obtained in Step 1 of Example 42 wassuspended in benzotrifluoride (10 mL). To the suspension were addedtert-butylamine (0.19 mL, 1.7 mmol) and p-toluenesulfonic anhydride (228mg, 0.698 mmol), and the mixture was stirred at room temperature for 18hours. To the reaction mixture were added tert-butylamine (0.19 mL, 1.7mmol) and p-toluenesulfonic anhydride (228 mg, 0.698 mmol) and themixture was further stirred at room temperature for 18 hours. Further,to the reaction mixture were added tert-butylamine (0.19 mL, 1.7 mmol)and p-toluenesulfonic anhydride (228 mg, 0.698 mmol) and the mixture wasfurther stirred at room temperature for 18 hours. A saturated aqueoussodium bicarbonate solution and water were added to the reactionmixture. Extraction with ethyl acetate and drying over anhydrous sodiumsulfate were performed. After filtration, the solvent in the filtratewas evaporated under reduced pressure. The residue was dissolved inbenzotrifluoride (2.0 mL) and trifluoroacetic acid (2.0 mL) and thesolution was stirred at 70° C. for 18 hours. The solvent was evaporatedunder reduced pressure, and a saturated aqueous sodium bicarbonatesolution and water were added to the residue. Extraction with ethylacetate and drying over anhydrous sodium sulfate were performed. Afterfiltration, the solvent in the filtrate was evaporated under reducedpressure. The residue was purified by silica gel column chromatography(chloroform/methanol=1/10) to give Compound 45 (83.2 mg, 54% yield).

ESIMS m/z: 442 (M+H)⁺.

¹H-NMR (270 MHz, CDCl₃, δ): 1.13 (t, J=7.4 Hz, 3H), 1.96-2.06 (m, 2H),4.55-4.59 (m, 2H), 6.69 (s, 1H), 6.58-6.70 (m, 1H), 6.83 (d, J=5.3 Hz,1H), 7.42-7.73 (m, 4H), 8.13 (d, J=5.3 Hz, 1H).

Example 44 N-(3-(2,2,2-trifluoro-1-(pyridin-4-yl)ethoxy)quinoxalin-2-yl)butane-1-sulfonamide (Compound 46 Step 1N-(3-(2,2,2-trifluoro-1-(pyridin-4-yl)ethoxy)quinoxalin-2-yl)-N-((2-(trimethylsilyl)ethoxy)methyl)butane-1-sulfonamide(Compound B6

According to Example 1, Compound B6 (410 mg, 31% yield) was obtainedfrom compound A6 (1.08 g, 2.52 mmol) obtained in Reference Example 6 andCompound A28 (405 mg, 2.29 mmol) obtained in Reference Example 28.

Step 2N-(3-(2,2,2-trifluoro-1-(pyridin-4-yl)ethoxy)quinoxalin-2-yl)butane-1-sulfonamide(Compound 46

According to the method in Step 2 of Example 40, Compound 46 (91.8 mg,74% yield) was obtained from Compound B6 (160 mg, 0.280 mmol) obtainedin Step 1.

ESIMS m/z: 441 (M+H)⁺.

Example 454-(1-(3-(butylsulfonamido)quinoxalin-2-yloxy)-2,2,2-trifluoroethyl)pyridine1-oxide (Compound 47

According to Example 2, Compound 47 (35.4 mg, 63% yield) was obtainedfrom Compound 46 (54.0 mg, 0.123 mmol) obtained in Example 44.

ESIMS m/z: 457 (M+H)⁺.

Example 46N-(3-(1-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-2,2,2-trifluoroethoxy)quinoxalin-2-yl)propane-1-sulfonamide(Compound 48

According to Example 1, Compound 48 (77.6 mg, 75% yield) was obtainedfrom Compound A1 (67.1 mg, 0.235 mmol) obtained in Reference Example 1and Compound A29 (50.0 mg, 0.214 mmol) obtained in Reference Example 29.

ESIMS m/z: 484 (M+H)⁺.

Example 47 N-methyl-N-(4-(2,2,2-trifluoro-1-(3-(propylsulfonamido)quinoxalin-2-yloxy)ethyl)pyridin-2-yl)acetamide (Compound 49) Step 1N-methyl-N-(4-(2,2,2-trifluoro-1-(3-(N-((2-(trimethylsilyl)ethoxy)methyl) propylsulfonamido)quinoxalin-2-yloxy)ethyl) pyridin-2-yl)acetamide (Compound B7

N-methylacetamide (0.097 mL, 1.30 mmol) was dissolved in dichloromethane(1.0 mL). To the solution were added at 0° C. 2,6-lutidine (0.30 mL, 2.5mmol) and oxalyl dichloride (0.11 mL, 1.30 mmol). After stirring at thesame temperature for 15 minutes, a solution of Compound B4 (145 mg,0.253 mmol) obtained in Step 1 of Example 42 in dichloromethane (1.0 mL)was added and the mixture was further stirred at room temperature for 18hours. A saturated aqueous sodium bicarbonate solution and water wereadded to the reaction mixture. Extraction with ethyl acetate and dryingover anhydrous sodium sulfate were performed. After filtration, thesolvent in the filtrate was evaporated under reduced pressure. Theresidue was purified by silica gel column chromatography(chloroform/methanol=1/10) to give Compound B7 (157 mg, 99% yield).

ESIMS m/z: 628 (M+H)⁺.

Step 2 N-methyl-N-(4-(2,2,2-trifluoro-1-(3-(propylsulfonamido)quinoxalin-2-yloxy)ethyl)pyridin-2-yl) acetamide (Compound 49

According to the method in Step 2 of Example 40, Compound 49 (98.8 mg,79% yield) was obtained from Compound B7 (157 mg, 0.250 mmol) obtainedin Step 1.

ESIMS m/z: 498 (M+H)⁺.

¹H-NMR (270 MHz, CDCl₃, S): 1.13 (t, J=7.3 Hz, 3H), 1.95-2.07 (m, 2H),2.18 (s, 3H), 3.44 (s, 3H), 3.80 (t, J=7.0 Hz, 2H), 6.76 (q, J=6.6 Hz,1H), 7.31-7.94 (m, 6H), 8.53 (d, J=5.1 Hz, 1H).

Example 48 1-cyclopropyl-N-(3-(2,2,2-trifluoro-1-(pyridin-4-yl)ethoxy)quinoxalin-2-yl)methanesulfonamide (Compound 50

According to the method in Example 40, Compound 50 (33.5 mg, 2 steps 64%yield) was obtained from Compound A8 (55.8 mg, 0.130 mmol) obtained inReference Example 8 and Compound A28 (21.0 mg, 0.119 mmol) obtained inReference Example 28.

ESIMS m/z: 439 (M+H)⁺.

Example 49 2-methyl-N-(3-(2,2,2-trifluoro-1-(pyridin-4-yl)ethoxy)quinoxalin-2-yl)propane-1-sulfonamide (Compound 51

According to the method in Example 40, Compound 51 (37.3 mg, 2 steps 66%yield) was obtained from Compound A7 (61.5 mg, 0.143 mmol) obtained inReference Example 7 and Compound A28 (23.0 mg, 0.130 mmol) obtained inReference Example 28.

ESIMS m/z: 441 (M+H)⁺.

Example 50 N-(3-(1-(2-cyanopyridin-4-yl)-2,2,2-trifluoroethoxy)quinoxalin-2-yl)butane-1-sulfonamide (Compound 52

According to the method in Example 42, Compound 52 (51.6 mg, 3 steps 70%yield) was obtained from Compound B6 (89.7 mg, 0.157 mmol) obtained inStep 1 of Example 44.

ESIMS m/z: 466 (M+H)⁺.

Example 51N-(3-(2,2,2-trifluoro-1-(2-methylimidazo[1,2-a]pyridin-7-yl)ethoxy)quinoxalin-2-yl)propane-1-sulfonamide(Compound 53

According to Example 40, Compound 53 (7.2 mg, 2 steps 40% yield) wasobtained from Compound A5 (35.8 mg, 0.0860 mmol) obtained in ReferenceExample 5 and Compound A30 (18.0 mg, 0.0780 mmol) obtained in ReferenceExample 30.

ESIMS m/z: 480 (M+H)⁺.

Example 52N-(3-(1-(2-(1H-imidazol-1-yl)pyridin-4-yl)-2,2,2-trifluoroethoxy)quinoxalin-2-yl)propane-1-sulfonamide(Compound 54 Step 1N-(3-(1-(2-(1H-imidazol-1-yl)pyridin-4-yl)-2,2,2-trifluoroethoxy)quinoxalin-2-yl)-N-((2-(trimethylsilyl)ethoxy)methyl)propane-1-sulfonamide (Compound B8

Compound B4 (137 mg, 0.240 mmol) obtained in Step 1 of Example 42 wassuspended in toluene (2.4 mL), 1,1′-sulfonyldiimidazole (190 mg, 0.960mmol) was added, and the mixture was refluxed for 6 days. A 1 mol/Laqueous sodium hydroxide solution was added to the reaction mixture.Extraction with dichloromethane and drying over anhydrous sodium sulfatewere performed. After filtration, the solvent in the filtrate wasevaporated under reduced pressure. The residue was purified by silicagel column chromatography (ethyl acetate: 100%) to give Compound B8(19.3 mg, 13% yield).

Step 2N-(3-(1-(2-(1H-imidazol-1-yl)pyridin-4-yl)-2,2,2-trifluoroethoxy)quinoxalin-2-yl)propane-1-sulfonamide(Compound 54

According to the method in Step 2 of Example 40, Compound 54 (13.1 mg,97%) was obtained from Compound B8 (17.0 mg, 0.0270 mmol) obtained inStep 1.

ESIMS m/z: 493 (M+H)⁺.

Example 53 N-(3-(2,2,2-trifluoro-1-(2-(methylthio)pyrimidin-5-yl)ethoxy)quinoxalin-2-yl)propane-1-sulfonamide (Compound 55

According to Example 1, Compound 55 (37.0 mg, 31% yield) was obtainedfrom Compound A1 (81.0 mg, 0.282 mmol) obtained in Reference Example 1and Compound A31 (57.5 mg, 0.256 mmol) obtained in Reference Example 31.

ESIMS m/z: 474 (M+H)⁺.

Example 54N-(3-(1-(2-(1,2,4-oxadiazol-3-yl)pyridin-4-yl)-2,2,2-trifluoroethoxy)quinoxalin-2-yl)propane-1-sulfonamide(Compound 56 Step 1N-(3-(1-(2-(1,2,4-oxadiazol-3-yl)pyridin-4-yl)-2,2,2-trifluoroethoxy)quinoxalin-2-yl)-N-((2-(trimethylsilyl)ethoxy)methyl)propane-1-sulfonamide (Compound B9)

Compound B5 (90.5 mg, 0.156 mmol) obtained in Step 2 of Example 42 wasdissolved in a 50% aqueous hydroxylamine solution (1.0 mL) and ethanol(1.0 mL) and the solution was stirred at room temperature for 30minutes. The solvent was evaporated under reduced pressure and theresidue was dissolved in triethyl orthoformate (1.0 mL). The mixture wasstirred at 100° C. for 23 hours and further stirred at 130° C. for 18hours. The solvent was evaporated under reduced pressure. The residuewas purified by silica gel column chromatography (hexane/ethylacetate=1/1) to give Compound B9 (67.7 mg, 70% yield).

Step 2N-(3-(1-(2-(1,2,4-oxadiazol-3-yl)pyridin-4-yl)-2,2,2-trifluoroethoxy)quinoxalin-2-yl)propane-1-sulfonamide(Compound 56

According to the method in Step 2 of Example 40, Compound 56 (34.0 mg,64% yield) was obtained from Compound B9 (67.7 mg, 0.108 mmol) obtainedin Step 1.

ESIMS m/z: 495 (M+H)⁺.

Example 55 N-(3-(1-(benzo[d][1,3]dioxol-5-yl)-2,2,2-trifluoroethoxy)quinoxalin-2-yl)propane-1-sulfonamide (Compound 57

According to Example 1, Compound 57 (65.0 mg, 32% yield) was obtainedfrom Compound A1 (138 mg, 0.482 mmol) obtained in Reference Example 1and Compound A32 (96.4 mg, 0.438 mmol) obtained in Reference Example 32.

ESIMS m/z: 470 (M+H)⁺.

Example 56 N-(3-(2,2,2-trifluoro-1-(2-(methylamino)pyrimidin-5-yl)ethoxy)quinoxalin-2-yl)propane-1-sulfonamide (Compound 58 Step 1N-(3-(2,2,2-trifluoro-1-(2-(methylthio)pyrimidin-5-yl)ethoxy)quinoxalin-2-yl)-N-((2-(trimethylsilyl)ethoxy)methyl)propane-1-sulfonamide(Compound B10

According to Example 1, Compound B10 (132 mg, 95%) was obtained fromCompound A5 (106 mg, 0.254 mmol) obtained in Reference Example 5 andCompound A31 (51.8 mg, 0.231 mmol) obtained in Reference Example 31.

ESIMS m/z: 604 (M+H)⁺.

Step 2 N-(3-(2,2,2-trifluoro-1-(2-(methylamino)pyrimidin-5-yl)ethoxy)quinoxalin-2-yl)-N-((2-(trimethylsilyl)ethoxy)methyl)propane-1-sulfonamide(Compound B11

Compound B10 (51.0 mg, 0.0840 mmol) obtained in Step 1 was dissolved indichloromethane (1.0 mL), 65% meta-chloroperbenzoic acid (38.9 mg, 0.169mmol) was added at 0° C., and the mixture was stirred at roomtemperature for 1 hour. A saturated aqueous sodium bicarbonate solutionwas added to the reaction mixture. Extraction with chloroform and dryingover anhydrous sodium sulfate were performed. After filtration, thesolvent in the filtrate was evaporated under reduced pressure and theresidue was dissolved in THF (1.0 mL). Methylamine (2 mol/L solution inTHF, 1.0 mL) was added and the mixture was stirred at room temperaturefor 18 hours. The solvent was evaporated under reduced pressure. Theresidue was purified by silica gel column chromatography (hexane/ethylacetate=1/1) to give Compound B11 (44.3 mg, 89% yield).

ESIMS m/z: 587 (M+H)⁺.

Step 3 N-(3-(2,2,2-trifluoro-1-(2-(methylamino)pyrimidin-5-yl)ethoxy)quinoxalin-2-yl)propane-1-sulfonamide (Compound 58

According to the method in Step 2 of Example 40, Compound 58 (25.0 mg,73% yield) was obtained from Compound B11 (44.3 mg, 0.076 mmol) obtainedin Step 2.

ESIMS m/z: 457 (M+H)⁺.

Example 57N-(3-(2,2,2-trifluoro-1-(1H-indazol-6-yl)ethoxy)quinoxalin-2-yl)propane-1-sulfonamide(Compound 59 Step 1 Tert-butyl6-(2,2,2-trifluoro-1-(3-(N-((2-(trimethylsilyl)ethoxy)methyl)propylsulfonamido)quinoxalin-2-yloxy)ethyl)-1H-indazole-1-carboxylate(Compound B12

According to the method in Step 1 of Example 40, Compound B12 (74.9 mg,68% yield) was obtained from Compound A5 (72.3 mg, 0.174 mmol) obtainedin Reference Example 5 and Compound A33 (50.0 mg, 0.158 mmol) obtainedin Reference Example 33.

Step 2N-(3-(2,2,2-trifluoro-1-(1H-indazol-6-yl)ethoxy)quinoxalin-2-yl)propane-1-sulfonamide(Compound 59

Compound B12 (74.9 mg, 0.108 mmol) obtained in Step 1 was dissolved indichloromethane (1 mL). Triethylsilane (0.52 mL, 3.2 mmol) andtrifluoroacetic acid (0.25 mL, 3.2 mmol) were added at 0° C. and themixture was stirred at room temperature for 18 hours. A saturatedaqueous sodium bicarbonate solution and water were added to the reactionmixture. Extraction with ethyl acetate and drying over anhydrous sodiumsulfate were performed. After filtration, the solvent in the filtratewas evaporated under reduced pressure. The residue was purified bysilica gel column chromatography (hexane/ethyl acetate=1/1) to giveCompound 59 (40.3 mg, 80% yield).

ESIMS m/z: 466 (M+H)⁺.

Example 58N-(3-(2,2,2-trifluoro-1-(1H-indazol-5-yl)ethoxy)quinoxalin-2-yl)propane-1-sulfonamide(Compound 60

According to Example 57, Compound 60 (34.8 mg, 2 steps 69% yield) wasobtained from Compound A5 (72.3 mg, 0.174 mmol) obtained in ReferenceExample 5 and Compound A34 (50.0 mg, 0.158 mmol) obtained in ReferenceExample 34.

ESIMS m/z: 466 (M+H)⁺.

Example 59N-(3-(2,2,2-trifluoro-1-(pyrimidin-5-yl)ethoxy)quinoxalin-2-yl)propane-1-sulfonamide(Compound 61

According to Example 40, Compound 61 (63.6 mg, 2 steps 81% yield) wasobtained from Compound A5 (84.5 mg, 0.203 mmol) obtained in ReferenceExample 5 and Compound A35 (32.8 mg, 0.184 mmol) obtained in ReferenceExample 35.

ESIMS m/z: 428 (M+H)⁺.

Example 60 N-(3-(2,2,2-trifluoro-1-(2-methylpyrimidin-5-yl)ethoxy)quinoxalin-2-yl)propane-1-sulfonamide (Compound 62

According to Example 40, Compound 62 (57.9 mg, 2 steps 77% yield) wasobtained from Compound A5 (124 mg, 0.298 mmol) obtained in ReferenceExample 5 and Compound A36 (52.0 mg, 0.271 mmol) obtained in ReferenceExample 36.

ESIMS m/z: 442 (M+H)⁺.

Example 61 N-(3-(2,2,2-trifluoro-1-(5-(methylsulfonyl)pyridin-3-yl)ethoxy)quinoxalin-2-yl)propane-1-sulfonamide (Compound 63

According to Example 13, Compound 63 (42.9 mg, 52% yield) was obtainedfrom Compound A13 (69.0 mg, 0.165 mmol) obtained in Reference Example13.

ESIMS m/z: 505 (M+H)⁺.

Example 62 N-(3-(2,2,2-trifluoro-1-(6-(2-methyl-2H-1,2,3-triazol-4-yl)pyridin-3-yl)ethoxy)quinoxalin-2-yl)propane-1-sulfonamide (Compounds 64,64A, and 64B

According to Example 1, Compound 64 (451 mg, 39% yield) was obtainedfrom Compound A1 (656 mg, 2.30 mmol) obtained in Reference Example 1 andCompound A43 (593 mg, 2.30 mmol) obtained in Reference Example 43.

Separation of Compound 64 by preparative high performance liquidchromatography in the same manner as in Example 66 gave the enantiomers,Compound 64A and Compound 64B. The compound with a shorter retentiontime is defined as Compound 64B, and the compound with a longerretention time is defined as Compound 64A.

Compound 64: ESIMS m/z: 508 (M+H)⁺.

Compound 64A: ESIMS m/z: 508 (M+H)⁺.

Compound 64B: ESIMS m/z: 508 (M+H)⁺.

Example 63N-(3-(2,2,2-trifluoro-1-(6-(oxazol-5-yl)pyridin-3-yl)ethoxy)quinoxalin-2-yl)propane-1-sulfonamide(Compound 65

According to Example 1, Compound 65 (23.0 mg, 18% yield) was obtainedfrom compound A1 (72.0 mg, 0.251 mmol) obtained in Reference Example 1and Compound A44 (61.4 mg, 0.251 mmol) obtained in Reference Example 44.

ESIMS m/z: 494 (M+H)⁺.

Example 64 N-(3-(2,2,2-trifluoro-1-(6-(5-methyl-1,2,4-oxadiazol-3-yl)pyridin-3-yl)ethoxy)quinoxalin-2-yl)propane-1-sulfonamide (Compound 66

According to Example 13, Compound 66 (54.5 mg, 32% yield) was obtainedfrom Compound A38 (143 mg, 0.339 mmol) obtained in Reference Example 38.

ESIMS m/z: 509 (M+H)⁺.

Example 652-methoxy-N-(3-(2,2,2-trifluoro-1-(6-(1-methyl-1H-pyrazol-5-yl)pyridin-3-yl)ethoxy)quinoxalin-2-yl)ethanesulfonamide(Compound 67

According to Example 13, Compound 67 (108 mg, 59% yield) was obtainedfrom Compound A39 (144 mg, 0.343 mmol) obtained in Reference Example 39.

ESIMS m/z: 523 (M+H)⁺.

Example 662-methoxy-N-(3-(2,2,2-trifluoro-1-(6-(2-methyl-2H-1,2,3-triazol-4-yl)pyridin-3-yl)ethoxy)quinoxalin-2-yl)ethanesulfonamide (Compounds 68, 68A, and 68B

According to Example 13, Compound 68 (449 mg, 68% yield) was obtainedfrom Compound A40 (528 mg, 1.26 mmol) obtained in Reference Example 40.

Separation of Compound 68 (980 mg) by preparative high performanceliquid chromatography [CHIRALPAK (registered trademark) IC (DaicelChemical Industries, Ltd.); particle size: 5 μm; 2 cm (internaldiameter)×25 cm (length); chloroform: 100%; flow rate: 5.7 mL/min;column oven temperature: 40° C.; detection wavelength: 304 nm] gave theenantiomers, Compound 68A (440 mg) and Compound 68B (450 mg). Thecompound with 16 minutes retention time is defined as Compound 68A, andthe compound with 30 minutes retention time is defined as Compound 68B.

Compound 68: ESIMS m/z: 524 (M+H)⁺.

Compound 68A: ESIMS m/z: 524 (M+H)⁺.

Compound 68B: ESIMS m/z: 524 (M+H)⁺.

Example 672-methoxy-N-(3-(2,2,2-trifluoro-1-(6-(2-methyl-1H-imidazol-1-yl)pyridin-3-yl)ethoxy)quinoxalin-2-yl)ethanesulfonamide(Compound 69

According to Example 13, Compound 69 (23.9 mg, 18% yield) was obtainedfrom Compound A41 (104 mg, 0.248 mmol) obtained in Reference Example 41.

ESIMS m/z: 523 (M+H)⁺.

Example 68N-(3-(1-(1,2-dimethyl-1H-imidazol-5-yl)-2,2,2-trifluoroethoxy)quinoxalin-2-yl)propane-1-sulfonamide(Compound 70

According to Example 1, Compound 70 (38.9 mg, 32%) was obtained fromCompound A1 (82.0 mg, 0.286 mmol) obtained in Reference Example 1 andCompound A45 (52.8 mg, 0.272 mmol) obtained in Reference Example 45.

ESIMS m/z: 444 (M+H)⁺.

Example 69 N-(3-(1-(2-acetylthiazol-5-yl)-2,2,2-trifluoroethoxy)quinoxalin-2-yl)propane-1-sulfonamide (Compound 71 Step 1N-(3-(1-(2-acetylthiazol-5-yl)-2,2,2-trifluoroethoxy)quinoxalin-2-yl)-N-((2-(trimethylsilyl)ethoxy)methyl)propane-1-sulfonamide (Compound B13

According to Example 1, Compound B13 (55.8 mg, 40%) was obtained fromCompound A5 (105 mg, 0.253 mmol) obtained in Reference Example 5 andCompound A46 (51.7 mg, 0.230 mmol) obtained in Reference Example 46.

Step 2 N-(3-(1-(2-acetylthiazol-5-yl)-2,2,2-trifluoroethoxy)quinoxalin-2-yl)propane-1-sulfonamide (Compound 71

According to Step 2 of Example 40, Compound 71 (43.2 mg, 99%) wasobtained from Compound B13 (55.8 mg, 0.092 mmol) obtained in Step 1.

ESIMS m/z: 475 (M+H)⁺.

Example 70 N-(3-(1-(2-acetylpyridin-4-yl)-2,2,2-trifluoroethoxy)quinoxalin-2-yl)-2-methoxyethanesulfonamide (Compound 72

According to Example 13, Compound 72 (78.1 mg, 29%) was obtained fromCompound A42 (211 mg, 0.552 mmol) obtained in Reference Example 42 and2-methoxyethanesulfonamide (115 mg, 0.828 mmol) obtained in Step 1 ofReference Example 37.

ESIMS m/z: 485 (M+H)⁺.

Example 712-methoxy-N-(3-(2,2,2-trifluoro-1-(6-(oxazol-5-yl)pyridin-3-yl)ethoxy)quinoxalin-2-yl)ethanesulfonamide(Compound 73 Step 12-methoxy-N-(3-(2,2,2-trifluoro-1-(6-(oxazol-5-yl)pyridin-3-yl)ethoxy)quinoxalin-2-yl)-N-((2-(trimethylsilyl)ethoxy)methyl)ethanesulfonamide(Compound B14

According to Example 1, Compound B14 (193 mg, 92%) was obtained fromCompound A37 (156 mg, 0.360 mmol) obtained in Reference Example 37 andCompound A44 (80.0 mg, 0.328 mmol) obtained in Reference Example 44.

Step 22-methoxy-N-(3-(2,2,2-trifluoro-1-(6-(oxazol-5-yl)pyridin-3-yl)ethoxy)quinoxalin-2-yl)ethanesulfonamide(Compound 73

According to Step 2 of Example 40, Compound 73 (146 mg, 95%) wasobtained from Compound B14 (193 mg, 0.302 mmol) obtained in Step 1.

ESIMS m/z: 510 (M+H)⁺.

Example 72 N-(3-(1-(2-acetylthiazol-5-yl)-2,2,2-trifluoroethoxy)quinoxalin-2-yl)-2-methoxyethanesulfonamide (Compound 74 Step 1N-(3-(1-(2-acetylthiazol-5-yl)-2,2,2-trifluoroethoxy)quinoxalin-2-yl)-2-methoxy-N-((2-(trimethylsilyl)ethoxy)methyl)ethanesulfonamide (Compound B15

According to Example 1, Compound B15 (93.0 mg, 48%) was obtained fromCompound A5 (109 mg, 0.253 mmol) obtained in Reference Example 5 andCompound A46 (51.7 mg, 0.230 mmol) obtained in Reference Example 46.

Step 2 N-(3-(1-(2-acetylthiazol-5-yl)-2,2,2-trifluoroethoxy)quinoxalin-2-yl)-2-methoxyethanesulfonamide (Compound 74

According to Step 2 of Example 40, Compound 74 (55.4 mg, 49%) wasobtained from Compound B15 (143 mg, 0.230 mmol) obtained in Step 1.

ESIMS m/z: 491 (M+H)⁺.

Example 73 N-(3-(2,2,2-trifluoro-1-(6-(1-methyl-1H-pyrazol-4-yl)pyridin-3-yl)ethoxy)quinoxalin-2-yl)propane-1-sulfonamide (Compounds 75and 76

Separation of Compound 32 obtained in Example 32 by preparative highperformance liquid chromatography in the same manner as in Example 66gave the enantiomers, Compounds 75 and 76. The compound with a shorterretention time is defined as Compound 75, and the compound with a longerretention time is defined as Compound 76.

Compound 75: ESIMS m/z: 507 (M+H)⁺.

Compound 76: ESIMS m/z: 507 (M+H)⁺.

Example 74 N-(7-iodo-3-(2,2,2-trifluoro-1-(pyridin-3-yl)ethoxy)quinoxalin-2-yl)propane-1-sulfonamide (Compound 77

According to Example 13, Compound 77 (725 mg, 73% yield) was obtainedfrom Compound A47 (222 mg, 1.81 mmol) obtained in Reference Example 47.

ESIMS m/z: 553 (M+H)⁺; 1H-NMR (270 MHz, CDCl₃, δ): 1.13 (t, J=7.3 Hz,3H), 1.93-2.05 (m, 2H), 3.66-3.85 (m, 2H), 6.76 (q, J=6.5 Hz, 1H),7.35-7.47 (m, 2H), 7.73-7.85 (m, 1H), 7.94 (d, J=8.1 Hz, 1H), 8.22-8.34(m, 1H), 8.69 (dd, J=4.9, 1.8 Hz, 1H), 8.87 (d, J=1.8 Hz, 1H).

Example 75 N-(7-cyano-3-(2,2,2-trifluoro-1-(pyridin-3-yl)ethoxy)quinoxalin-2-yl)propane-1-sulfonamide (Compound 78

Compound 77 (41.0 mg, 0.074 mmol) obtained in Example 74 was dissolvedin DMA (1.60 mL). To the solution were added zinc cyanide (21.8 mg, 1.11mmol), zinc (1.17 mg, 0.018 mmol), tris(dibenzylideneacetone)dipalladium(2.72 mg, 0.003 mmol) and 1,1′-bis(diphenylphosphino)ferrocene (2.67 mg,0.005 mmol), and the mixture was stirred at 120° C. for 1 hour. Waterwas added to the reaction mixture and the mixture was filtered throughCelite. The filtrate was extracted with ethyl acetate. Washing withsaturated brine and drying over anhydrous magnesium sulfate wereperformed. After filtration, the solvent in the filtrate was evaporatedunder reduced pressure. The residue was purified by silica gel columnchromatography (hexane/ethyl acetate=1/0 to 2/3) to give Compound 78(14.0 mg, 42% yield).

ESIMS m/z: 452 (M+H)⁺; ¹H-NMR (270 MHz, CDCl₃, 8): 1.14 (t, J=7.3 Hz,3H), 1.93-2.09 (m, 2H), 3.68-3.84 (m, 2H), 6.79 (q, J=6.4 Hz, 1H), 7.42(dd, J=7.9, 4.9 Hz, 1H), 7.69-7.85 (m, 2H), 7.95 (d, J=7.9 Hz, 1H),8.19-8.28 (m, 1H), 8.71 (dd, J=4.9, 1.8 Hz, 1H), 8.88 (d, J=1.8 Hz, 1H).

Example 76 N-(7-ethynyl-3-(2,2,2-trifluoro-1-(pyridin-3-yl)ethoxy)quinoxalin-2-yl)propane-1-sulfonamide (Compound 79

Compound 77 (70.0 mg, 0.127 mmol) obtained in Example 74 was dissolvedin DMF (2.00 mL). To the solution were added trimethylsilylacetylene(0.089 mL, 0.634 mmol), triethylamine (0.088 mL, 0.634 mmol), copperiodide (I) (9.66 mg, 0.051 mmol), andtetrakis(triphenylphosphine)palladium (29.3 mg, 0.025 mmol), and themixture was stirred at 120° C. for 30 minutes. Water was added to thereaction mixture and the mixture was filtered through Celite. Thefiltrate was extracted with ethyl acetate. Washing with saturated brineand drying over anhydrous magnesium sulfate were performed. Afterfiltration, the solvent in the filtrate was evaporated under reducedpressure. The resulting residue was purified by silica gel columnchromatography (hexane/ethyl acetate=1/0 to 2/3). The obtained purifiedproduct was dissolved in THF (1.80 mL). Tetrabutylammonium fluoride (1.0mol/L solution in THF, 0.107 mL, 0.107 mmol) was added and the mixturewas stirred at room temperature for 2 hours. Water was added to thereaction mixture. Extraction with ethyl acetate, washing with saturatedbrine and drying over anhydrous magnesium sulfate were performed. Afterfiltration, the solvent in the filtrate was evaporated under reducedpressure. The resulting residue was purified by silica gel columnchromatography (hexane/ethyl acetate=1/0 to 1/1) to give Compound 79(25.7 mg, 46% yield). ESIMS m/z: 451 (M+H)⁺; ¹H-NMR (270 MHz, CDCl₃, 5):1.13 (t, J=7.5 Hz, 3H), 1.92-2.07 (m, 2H), 3.20 (s, 1H), 3.69-3.84 (m,2H), 6.78 (q, J=6.0 Hz, 1H), 7.32-7.50 (m, 1H), 7.55-7.72 (m, 2H), 7.95(d, J=8.4 Hz, 1H), 8.00-8.08 (m, 1H), 8.45-9.10 (m, 2H).

Example 77

Tablets having the following composition were prepared in a usualmanner. An amount of 40 g of Compound 3 was mixed with 286.8 g oflactose and 60 g of potato starch. To the mixture was added 120 g of a10% aqueous hydroxypropyl cellulose solution. This mixture was kneaded,granulated, dried, and fine-granulated in a usual manner to preparegranules for tableting. To the mixture was added 1.2 g of magnesiumstearate and the mixture was mixed in a usual manner. The mixture wastableted with a tableting machine (Kikusui, Model RT-15) equipped with apestle, whose diameter is 8 mm, to give tablets (containing 20 mg of theactive ingredient per tablet).

Formula Compound 3 20 mg Lactose 143.4 mg Potato starch 30 mgHydroxypropyl cellulose 6 mg Magnesium stearate 0.6 mg 200 mg

Example 78

Injections having the following composition were prepared in a usualmanner. An amount of 1 g of Compound 8 was added to distilled water forinjection and mixed. The pH was adjusted to 7 by adding hydrochloricacid and an aqueous sodium hydroxide solution, and the total volume wasmade up to 1000 mL with distilled water for injection. Two mL of themixture was aseptically packed into each glass vial, and thus injections(containing 2 mg of the active ingredient per vial) were obtained.

Formula Compound 8 2 mg Hydrochloric acid q.s. Aqueous sodium hydroxidesolution q.s. Distilled water for injection q.s. 2.00 mL

INDUSTRIAL APPLICABILITY

The present invention provides a nitrogen-containing heterocycliccompound having an inhibitory effect on the production of kynurenine ora pharmaceutically acceptable salt thereof; a kynurenine productioninhibitor comprising one or more of said compound or salt thereof as anactive ingredient; and the like.

1-20. (canceled)
 21. A nitrogen-containing heterocyclic compound:

or a pharmacologically acceptable salts thereof.
 22. A pharmaceuticalcomposition comprising, as an active ingredient, the nitrogen-containingheterocyclic compound or a pharmaceutically acceptable salt thereof ofclaim
 21. 23. A kynurenine production inhibitor comprising, as an activeingredient, the nitrogen-containing heterocyclic compound or apharmaceutically acceptable salt thereof of claim
 21. 24. A method forinhibiting the production of kynurenine, comprising a step ofadministering an effective amount of the nitrogen-containingheterocyclic compound or a pharmaceutically acceptable salt thereof ofclaim
 21. 25. A preventive or therapeutic agent for a disease involvingthe production of kynurenine, comprising, as an active ingredient, thenitrogen-containing heterocyclic compound or a pharmaceuticallyacceptable salt thereof of claim
 21. 26. A method for preventing ortreating a disease involving the production of kynurenine, comprising astep of administering an effective amount of the nitrogen-containingheterocyclic compound or a pharmaceutically acceptable salt thereof ofclaim
 21. 27. A method of producing a pharmaceutical composition fortreating for the manufacture of a preventive or therapeutic agent for adisease involving the production of kynurenine comprising, mixing thenitrogen-containing heterocyclic compound or a pharmaceuticallyacceptable salt thereof of claim 21 with a pharmaceutically acceptablecarrier.
 28. The method of claim 26, wherein the disease involving theproduction of kynurenine is selected from the group consisting of cancer(tumor), immune diseases, neurodegenerative diseases, and an infection.29. The method of claim 28, wherein the disease involving the productionof kynurenine is cancer (tumor).
 30. The method of claim 29, wherein thecancer (tumor) is selected from the group consisting of a hematopoietictumor, multiple myeloma, breast cancer, ovarian cancer, endometrialcancer, cervical cancer, prostate cancer, bladder cancer, renal cancer,gastric cancer, esophagus cancer, hepatic cancer, biliary tract cancer,colon cancer, rectal cancer, pancreatic cancer, lung cancer, head andneck cancer, osteosarcoma, melanoma, and brain tumor.
 31. The method ofclaim 30, wherein the cancer (tumor) is a hematopoietic tumor ormultiple myeloma.
 32. The method of claim 28, wherein the diseaseinvolving the production of kynurenine is an infection.
 33. The methodof claim 32, wherein the infection is selected from the group consistingof a viral infection, bacterial infection, fungal infection, chlamydialinfection, and rickettsial infection.
 34. The method of claim 33,wherein the infection is a viral infection.
 35. The method of claim 28,wherein the disease involving the production of kynurenine is an immunedisease.